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Clinical Transplantation 2013Antithymocyte globulin (ATG) has shown efficacy in preventing acute GVHD (aGVHD) in allogeneic hematopoietic cell transplantation (allo-HCT), but its efficacy in chronic... (Meta-Analysis)
Meta-Analysis Review
Long-term outcomes of antithymocyte globulin in patients with hematological malignancies undergoing myeloablative allogeneic hematopoietic cell transplantation: a systematic review and meta-analysis.
Antithymocyte globulin (ATG) has shown efficacy in preventing acute GVHD (aGVHD) in allogeneic hematopoietic cell transplantation (allo-HCT), but its efficacy in chronic GVHD (cGVHD) and long-term outcomes remains controversial. We conducted a systematic review and meta-analysis to evaluate potential benefit and risk of prophylactic ATG use in myeloablative HCT. We searched Pubmed, EMBASE, Cochrane databases, and included 10 trials (two RCTs and eight retrospective) comparing ATG use vs. control with a total of 1859 patients. The median follow-ups were over two yr. Outcomes assessed included overall cGVHD, extensive cGVHD, overall survival (OS), disease-free survival, relapse, and causes of death. Our results showed ATG significantly decreased overall cGVHD (RR = 0.59; 95% CI: 0.53-0.66, p < 0.00001), extensive cGVHD (RR = 0.34; 95% CI: 0.25-0.47, p < 0.00001). Pooled results also showed ATG use was associated with a marginal increased risk of relapse (RR = 1.28; 95% CI: 1.01-1.63, p = 0.04), and a non-inferior OS (HR = 0.86; 95% CI: 0.74-1.01, p = 0.06). We conclude prophylactic use of ATG exerts a favorable effect in reducing cGVHD without survival impairment in a long term, although a higher relapse rate is a major threat.
Topics: Antilymphocyte Serum; Chronic Disease; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Models, Statistical; Postoperative Complications; Transplantation, Homologous; Treatment Outcome
PubMed: 23383989
DOI: 10.1111/ctr.12091 -
The Cochrane Database of Systematic... Sep 2012Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment for many malignant and non-malignant haematological disorders. Graft-versus-host... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment for many malignant and non-malignant haematological disorders. Graft-versus-host disease (GVHD), a condition frequently occurring after HSCT, is the result of host tissues being attacked by donor immune cells. One strategy for the prevention of GVHD is the administration of anti-thymocyte globulins (ATG), a set of polyclonal antibodies directed against a variety of immune cell epitopes, leading to immunosuppression and immunomodulation.
OBJECTIVES
To assess the effect of ATG used for the prevention of graft-versus-host disease (GVHD) in patients undergoing allogeneic HSCT with regard to overall survival, incidence and severity of acute and chronic GVHD, incidence of relapse, incidence of infectious complications, non-relapse mortality, early mortality within 100 days of transplantation, progression-free survival, quality of life and adverse events.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (January 1950 to February 2012), trials registries and conference proceedings. The search was conducted in October 2010 and was updated in July 2011 and February 2012. We did not apply any language restrictions.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) investigating the impact of ATG on GVHD prophylaxis in adults suffering from haematological diseases and undergoing allogeneic HSCT. Treatment arms had to differ only in the addition of ATG to the standard GVHD prophylaxis regimen.
DATA COLLECTION AND ANALYSIS
Two review authors screened abstracts, extracted data and analysed the data independently. We contacted study authors for additional information.
MAIN RESULTS
We included in the meta-analysis six RCTs which met the pre-defined selection criteria, involving a total of 568 participants. Quality of data reporting was heterogeneous among these studies with a lack of detailed information in the early studies.The primary outcome of overall survival was not significantly changed by the addition of ATG for the prophylaxis of GVHD (harms ratio (HR) 0.88; 95% CI 0.67 to 1.15, P = 0.33).The incidence of treatment-requiring or severe acute GVHD (grade II to IV) was significantly lower in patients who received ATG (risk ratio (RR) 0.68; 95% CI 0.55 to 0.85, P = 0.009; number needed to treat (NNT) 8). Also, the incidence of severe acute GVHD (grade III to IV) was significantly reduced (HR 0.53; 95% CI 0.33 to 0.85, P = 0.0005; NNT 7) but comparable data were available for rabbit ATG only. However, pooled study results regarding the incidence of acute GVHD of all grades (I to IV) showed no significant benefit of ATG treatment (RR 0.89; 95% CI 0.74 to 1.06, P = 0.20).Meta-analysis of data regarding the incidence of overall chronic GVHD (both, limited and extensive) was not possible. Nevertheless, studies reporting on extensive chronic GVHD (only studies evaluating rabbit ATG) suggested a lower incidence of extensive chronic GVHD whereas others that only reported on overall chronic GVHD did not show an advantage for ATG.Pooled results regarding the incidence of relapse were not significantly different (RR 1.13; 95% CI 0.75 to 1.68, P = 0.56), as well as pooled results regarding non-relapse mortality (HR 0.82; 95% CI 0.55 to 1.24, P = 0.35).Due to the lack of comparable data, we could not perform meta-analysis of data regarding the incidence of chronic GVHD, relapse-related mortality, progression-free survival, quality of life, adverse events and engraftment.
AUTHORS' CONCLUSIONS
Our systematic review suggests that the addition of ATG during allogeneic HSCT significantly reduces the incidence of severe grades (II to IV) of acute GvHD, whereas the incidence of overall acute GVHD (grades I to IV) was not significantly lowered. This indicates a reduction of the severity but not the incidence of acute GVHD. However, this effect did not lead to a significant improvement of overall survival, which may be due to the severe potential side effects of the consecutively increased immunosuppression.Furthermore, future research is needed to clarify the effect of ATG on the incidence and severity of chronic GVHD and consequently on all aspects of quality of life.From the currently available data, no recommendation on the general use of ATG in allogeneic HSCT can be supported. Therefore, a careful consideration of the use of ATG based on the patient's condition and the risk factors of the transplantation setting should be made.
Topics: Acute Disease; Adult; Antilymphocyte Serum; Bone Marrow Transplantation; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Randomized Controlled Trials as Topic; Recurrence; Transplantation, Homologous
PubMed: 22972135
DOI: 10.1002/14651858.CD009159.pub2 -
Transplant Immunology Oct 2012To compare the efficacy and safety of alemtuzumab versus traditional antibodies for induction therapy in renal transplantation. (Comparative Study)
Comparative Study Meta-Analysis Review
OBJECTIVE
To compare the efficacy and safety of alemtuzumab versus traditional antibodies for induction therapy in renal transplantation.
METHODS
Literature searches for all randomized controlled trials comparing alemtuzumab with traditional antibodies for post renal transplant induction therapy were performed using MEDLINE, EMBASE and the Cochrane Library. Quality assessment was performed in each trial. Meta-analyses were performed to demonstrate the pooled effects of relative risk (RR) with 95% confidence intervals (CI).
RESULTS
A total of 808 participants from six randomized controlled trials (RCTs) were included. Alemtuzumab was associated with lower incidence of biopsy-proven acute rejection over traditional antibodies (RR 0.63, CI 0.45-0.87, p=0.005). This difference remained when only studies comparing alemtuzumab with rabbit antithymocyte globulin were included (RR 0.32, CI 0.11-0.91, p=0.03), but lost significance when only patients at high-risk were included (RR 0.86, CI 0.48-1.55, p=0.62). No significant differences were detected between alemtuzumab and traditional antibodies in terms of delayed graft function, patient death, graft loss, and safety profile.
CONCLUSIONS
Alemtuzumab induction is superior to traditional antibodies in preventing AR in renal transplantation, but this benefit may not extend to recipients at high immunologic risk. The lower rejection rates do not translate into a uniform increase in graft or patient survival.
Topics: Acute Disease; Alemtuzumab; Animals; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Neoplasm; Antilymphocyte Serum; CD52 Antigen; Glycoproteins; Graft Rejection; Humans; Immune Tolerance; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Rabbits; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 22960043
DOI: 10.1016/j.trim.2012.08.006 -
Leukemia Apr 2012Graft-versus-host-disease (GVHD) is a major complication associated with allogeneic hematopoietic cell transplantation (allo-HCT). Antithymocyte globulin (ATG) is... (Review)
Review
Graft-versus-host-disease (GVHD) is a major complication associated with allogeneic hematopoietic cell transplantation (allo-HCT). Antithymocyte globulin (ATG) is recommended for GVHD prophylaxis following allo-HCT, however, evidence on efficacy of ATG is conflicting. Accordingly, we undertook a systematic review. All phase III randomized controlled trials (RCTs) comparing ATG versus control for prevention of GVHD in patients undergoing allo-HCT were eligible. Medline and Cochrane databases were searched. Data on methodological quality, benefits and harms were extracted for each trial and pooled under a random effects model. Seven RCTs enrolling 733 patients met inclusion criteria. Pooled results showed no difference for overall survival with use of ATG (hazard ratio was 0.91; 95% confidence intervals (CI), 0.75-1.10; P = 0.32). There was a significant benefit for prevention of grade III/IV acute GVHD (risk ratio (RR) = 0.51; 95% CI, 0.27-0.94; P = 0.03). There was no benefit associated with ATG use for prevention of either grade II (RR = 0.79; 95% CI, 0.48-1.30; P = 0.35) or grade I acute GVHD (RR = 1.42; 95% CI, 0.75-2.69; P = 0.28). Use of ATG was not associated with significant reduction in non-relapse mortality (RR = 0.74; 95% CI, 0.53-1.03; P = 0.08). Future trials with adequate sample size are required to provide more definitive answers.
Topics: Antilymphocyte Serum; Clinical Trials, Phase III as Topic; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Randomized Controlled Trials as Topic; Transplantation, Homologous
PubMed: 22182922
DOI: 10.1038/leu.2011.349 -
Transplantation Proceedings Jun 2011Posttransplantation lymphoproliferative disorder (PTLD) is an important complication of transplantation. Risk factors include increased overall immunosuppression... (Review)
Review
Posttransplantation lymphoproliferative disorder (PTLD) is an important complication of transplantation. Risk factors include increased overall immunosuppression exposure and inadequate antiviral prophylaxis; however, the effects of T-cell-depleting agents on PTLD are unclear. A systematic literature review was conducted to assess PTLD in clinical studies published 1999-2009 in transplant patients with ≥ 3 years follow-up who received Thymoglobulin for induction. Twenty studies were identified (12 kidney, 7 heart, and 1 liver), of which 3 were excluded for insufficient PTLD reporting. The final study group comprised 2,246 kidney and heart transplant recipients (liver study excluded) who received Thymoglobulin. At a median follow-up of 5 years, the incidence of PTLD was 0.98% (kidney, 0.93%; heart, 1.05%) among Thymoglobulin-treated patients. The cumulative Thymoglobulin dose reported in these studies was not associated with the development of PTLD (P = NS). However, incidence of PTLD was significantly lower with antiviral prophylaxis (0.63%) than without (1.87%; P = .013). Heart transplant recipients not receiving antiviral prophylaxis had the highest PTLD incidence, possibly attributable to a greater overall immunosuppressive burden. This analysis revealed that PTLD incidences in kidney and heart transplant recipients receiving Thymoglobulin were low overall and perhaps related more to concomitant anti-viral prophylaxis use.
Topics: Antilymphocyte Serum; Heart Transplantation; Humans; Kidney Transplantation; Lymphoproliferative Disorders
PubMed: 21693205
DOI: 10.1016/j.transproceed.2011.03.036 -
Acta Haematologica 2008Immunosuppression is the therapeutic alternative for patients with aplastic anemia who are ineligible for allogeneic transplant. We aimed to assess the benefit of the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Immunosuppression is the therapeutic alternative for patients with aplastic anemia who are ineligible for allogeneic transplant. We aimed to assess the benefit of the combination of antithymocyte globulin (ATG) and cyclosporine (CsA).
METHODS
We performed a systematic review and meta-analysis of all randomized controlled trials that compared ATG and CsA to ATG alone as first-line treatment for patients with severe and nonsevere aplastic anemia. The Cochrane Library, Medline, conference proceedings and references were searched until 2008. Relative risks (RR) with 95% confidence intervals (CIs) were estimated for each trial and pooled.
RESULTS
Our search yielded 4 trials. For patients with severe aplastic anemia, there was a significant reduction in mortality in the ATG and CsA arm, which began at 3 months (RR = 0.50, 95% CI 0.29-0.85) and was maintained over a long follow-up of 5 years (RR = 0.58, 95 % CI 0.36-0.93). Conversely, in patients with nonsevere aplastic anemia, there was no difference in mortality.
CONCLUSIONS
The combination of both drugs should be considered the gold standard only for patients with severe aplastic anemia.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Aplastic; Antilymphocyte Serum; Child; Child, Preschool; Cyclosporine; Drug Therapy, Combination; Humans; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 19246887
DOI: 10.1159/000203403 -
The Cochrane Database of Systematic... Apr 2006Registry data shows that between 15-35% kidney recipients will undergo treatment for at least one episode of acute rejection within the first post transplant year.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Registry data shows that between 15-35% kidney recipients will undergo treatment for at least one episode of acute rejection within the first post transplant year. Treatment options include pulsed steroid therapy, the use of an antibody preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the US, 61.4% patients with an acute rejection episode received steroids, 20.4% received an antibody preparation and 18.2% received both.
OBJECTIVES
To determine the benefits and harms of mono- or polyclonal antibodies (Ab) used to treat acute rejection in kidney transplant recipients.
SEARCH STRATEGY
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library, issue 2, 2005), MEDLINE (1966-June 2005), EMBASE (1980-June 2005), and the specialised register of the Cochrane Renal Group (June 2005).
SELECTION CRITERIA
Randomised controlled trials (RCTs) in all languages comparing all mono- and polyclonal antibody preparations, given in combination with any other immunosuppressive agents, for the treatment of acute graft rejection, when compared to any other treatment for acute rejection.
DATA COLLECTION AND ANALYSIS
Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as relative risk (RR) with 95% confidence intervals (CI).
MAIN RESULTS
Twenty one trials (49 reports, 1387 patients) were identified. Trials were generally small, incompletely reported, especially for potential harms, and did not define outcome measures adequately. Fourteen trials (965 patients) compared therapies for first rejection episodes. Ab was better than steroid in reversing rejection (RR 0.57, 95% CI 0.38 to 0.87) and preventing graft loss (death censored RR 0.74, CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection or death at one year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection. There was no benefit of muromonab-CD3 over ATG or ALG in either reversing rejection, preventing subsequent rejection, preventing graft loss or death.
AUTHORS' CONCLUSIONS
In reversing first rejection, any antibody is better than steroid and also prevents graft loss, but subsequent rejection and patient survival are not significantly different. In reversing steroid-resistant rejection the effects of different antibodies are also not significantly different. Given the clinical problem caused by acute rejection, data are very sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed.
Topics: Acute Disease; Antibodies; Antibodies, Monoclonal; Antilymphocyte Serum; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Randomized Controlled Trials as Topic
PubMed: 16625610
DOI: 10.1002/14651858.CD004756.pub3