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Medicine Jul 2017Alemtuzumab (ALEM) is widely used as an induction therapy for organ transplantation, and numerous randomized controlled trials (RCTs) have been published to evaluate its... (Comparative Study)
Comparative Study Meta-Analysis Review
Alemtuzumab (ALEM) is widely used as an induction therapy for organ transplantation, and numerous randomized controlled trials (RCTs) have been published to evaluate its efficacy and safety in kidney transplantation as compared with antithymocyte globulin (ATG). The purpose of this study was to compare the benefits and safety of ALEM with those of ATG for induction therapy.A systematic literature search in three electronic databases, including PubMed, EmBase, and Cochrane Library, since inception through October 2016, was conducted to identify potential RCTs for inclusion. Trials that investigated the risk of biopsy-proven acute rejection (BPAR), mortality, graft failure, delayed graft function (DGF), chronic allograft nephropathy (CAN), infections, cytomegalovirus (CMV) infections, new-onset diabetes mellitus after transplant (NODAT), and granulocyte colony stimulation factor (GCSF) use in kidney transplant recipients who received ALEM or ATG as an induction therapy were included. Relative risk (RR) and 95% confidence intervals (CIs) were calculated using a random-effects model.Six RCTs involving 446 kidney transplantation patients were included in this meta-analysis. The effects of ALEM therapy were not significantly different from those of ATG therapy, including the incidence of BPAR (RR: 0.77; 95% CI: 0.51-1.18; P = .229), mortality (RR: 0.64; 95% CI: 0.30-1.39; P = .263), graft failure (RR: 0.81; 95% CI: 0.49-1.33; P = .411), DGF (RR: 1.00; 95% CI: 0.60-1.67; P = .999), CAN (RR: 1.42; 95% CI: 0.44-4.57; P = .556), infections (RR: 1.00; 95% CI: 0.74-1.35; P = .989), CMV infections (RR: 0.70; 95% CI: 0.38-1.30; P = .263), NODAT (RR: 0.50; 95% CI: 0.18-1.36; P = .174), and GCSF use (RR: 1.16; 95% CI: 0.81-1.66; P = .413). Sensitivity analyses were consistent with the overall analysis for all effects except CAN, suggesting that the risk of CAN might be higher with ALEM therapy than ATG therapy (RR: 2.45; 95% CI: 1.02-5.94; P = .046).The findings of this study suggest that the beneficial effects of ALEM therapy are greater than those of ATG therapy in kidney transplantation patients; however, the effects were not statistically significant because of the limited number of trials. Further large-scale RCTs are needed to verify the treatment effects of ALEM.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Transplantation; Randomized Controlled Trials as Topic
PubMed: 28700465
DOI: 10.1097/MD.0000000000007151 -
Health Technology Assessment... Aug 2016End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal... (Review)
Review
BACKGROUND
End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival.
OBJECTIVES
To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation.
METHODS
Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death.
RESULTS
Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY.
LIMITATIONS
For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled.
FUTURE WORK
High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome.
CONCLUSION
Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42014013189.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Abatacept; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Bayes Theorem; Cost-Benefit Analysis; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Models, Economic; Mycophenolic Acid; Quality of Life; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Technology Assessment, Biomedical
PubMed: 27578428
DOI: 10.3310/hta20620 -
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 -
Biology of Blood and Marrow... Dec 2017Since 2000, various phase III randomized controlled trials (RCTs) have investigated the efficacy of rabbit antithymocyte globulin (ATG) in patients following allogeneic... (Comparative Study)
Comparative Study Meta-Analysis Review
Since 2000, various phase III randomized controlled trials (RCTs) have investigated the efficacy of rabbit antithymocyte globulin (ATG) in patients following allogeneic stem cell transplantation (allo-SCT). Comparisons of different ATG formulations are lacking, however. Our aim was to synthesize all published efficacy evidence to enable a comparison of all available formulations of rabbit ATG in the allo-SCT setting. We performed a systematic literature review to identify all available phase III RCT evidence. We searched the Cochrane Library, MEDLINE, MEDLINE In-Process, and the website www.ClinicalTrials.gov. In addition, a trial presented at the Annual Meeting of the American Society of Hematology 2016 was added to include the most recent evidence. We identified a total of 6 RCTs, including 2 formulations: anti-T lymphocyte globulin (ATLG; Grafalon, Neovii Biotech, Lexington, MA) and polyclonal globulin immunized with human thymocytes (Thymoglobulin [Thymo]; Genzyme-Sanofi, Cambridge, MA). The evidence was synthesized using a conventional network meta-analysis (NMA). The best treatment for preventing graft-versus-host disease (GVHD) was ATLG, which had a more favorable hazard ratio (HR) compared with standard treatment (chronic GVHD: HR, .42; 95% confidence interval [CI], .31 to .56; acute GVHD grade II-IV: HR, .54; 95% CI, .39 to .73; acute GVHD grade III-IV: HR, .50; 95% CI, .29 to .86), whereas both ATLG and Thymo were at least similarly effective in terms of transplantation-related mortality (TRM) (ATLG: HR, .90; 95% CI, .61 to 1.32; Thymo: HR, .90; 95% CI, .56 to 1.44). Thymo tended to be the better treatment option regarding overall survival (OS) (HR, .86; 95% CI, .59 to 1.26). Our NMA provides the first report of the relative efficacy of all available rabbit ATG formulations in patients undergoing allo-SCT. Until additional data from randomized head-to-head comparisons are available, based on the present analysis, ATLG seems to be the best option to prevent chronic and acute GVHD. Both formulations show similar efficacy in terms of TRM, whereas Thymo appears to be the better treatment option in terms of OS.
Topics: Animals; Antilymphocyte Serum; Graft vs Host Disease; Humans; Network Meta-Analysis; Rabbits; Randomized Controlled Trials as Topic; Stem Cell Transplantation; Survival Rate; Transplantation, Homologous
PubMed: 28864138
DOI: 10.1016/j.bbmt.2017.08.027 -
The Cochrane Database of Systematic... Jan 2017Prolonging kidney transplant survival is an important clinical priority. Induction immunosuppression with antibody therapy is recommended at transplantation and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Prolonging kidney transplant survival is an important clinical priority. Induction immunosuppression with antibody therapy is recommended at transplantation and non-depleting interleukin-2 receptor monoclonal antibodies (IL2Ra) are considered first line. It is suggested that recipients at high risk of rejection should receive lymphocyte-depleting antibodies but the relative benefits and harms of the available agents are uncertain.
OBJECTIVES
We aimed to: evaluate the relative and absolute effects of different antibody preparations (except IL2Ra) when used as induction therapy in kidney transplant recipients; determine how the benefits and adverse events vary for each antibody preparation; determine how the benefits and harms vary for different formulations of antibody preparation; and determine whether the benefits and harms vary in specific subgroups of recipients (e.g. children and sensitised recipients).
SEARCH METHODS
Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant.
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data and assessed risk of bias. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) together with their 95% confidence intervals (CI).
MAIN RESULTS
We included 99 studies (269 records; 8956 participants; 33 with contemporary agents). Methodology was incompletely reported in most studies leading to lower confidence in the treatment estimates.Antithymocyte globulin (ATG) prevented acute graft rejection (17 studies: RR 0.63, 95% CI 0.51 to 0.78). The benefits of ATG on graft rejection were similar when used with (12 studies: RR 0.61, 0.49 to 0.76) or without (5 studies: RR 0.65, 0.43 to 0.98) calcineurin inhibitor (CNI) treatment. ATG (with CNI therapy) had uncertain effects on death (3 to 6 months, 3 studies: RR 0.41, 0.13 to 1.22; 1 to 2 years, 5 studies: RR 0.75, 0.27 to 2.06; 5 years, 2 studies: RR 0.94, 0.11 to 7.81) and graft loss (3 to 6 months, 4 studies: RR 0.60, 0.34 to 1.05; 1 to 2 years, 3 studies: RR 0.65, 0.36 to 1.19). The effect of ATG on death-censored graft loss was uncertain at 1 to 2 years and 5 years. In non-CNI studies, ATG had uncertain effects on death but reduced death-censored graft loss (6 studies: RR 0.55, 0.38 to 0.78). When CNI and older non-CNI studies were combined, a benefit was seen with ATG at 1 to 2 years for both all-cause graft loss (7 studies: RR 0.71, 0.53 to 0.95) and death-censored graft loss (8 studies: RR 0.55, 0.39 to 0.77) but not sustained longer term. ATG increased cytomegalovirus (CMV) infection (6 studies: RR 1.55, 1.24 to 1.95), leucopenia (4 studies: RR 3.86, 2.79 to 5.34) and thrombocytopenia (4 studies: RR 2.41, 1.61 to 3.61) but had uncertain effects on delayed graft function, malignancy, post-transplant lymphoproliferative disorder (PTLD), and new onset diabetes after transplantation (NODAT).Alemtuzumab was compared to ATG in six studies (446 patients) with early steroid withdrawal (ESW) or steroid minimisation. Alemtuzumab plus steroid minimisation reduced acute rejection compared to ATG at one year (4 studies: RR 0.57, 0.35 to 0.93). In the two studies with ESW only in the alemtuzumab arm, the effect of alemtuzumab on acute rejection at 1 year was uncertain compared to ATG (RR 1.27, 0.50 to 3.19). Alemtuzumab had uncertain effects on death (1 year, 2 studies: RR 0.39, 0.06 to 2.42; 2 to 3 years, 3 studies: RR 0.67, 95% CI 0.15 to 2.95), graft loss (1 year, 2 studies: RR 0.39, 0.13 to 1.30; 2 to 3 years, 3 studies: RR 0.98, 95% CI 0.47 to 2.06), and death-censored graft loss (1 year, 2 studies: RR 0.38, 0.08 to 1.81; 2 to 3 years, 3 studies: RR 2.45, 95% CI 0.67 to 8.97) compared to ATG. Creatinine clearance was lower with alemtuzumab plus ESW at 6 months (2 studies: MD -13.35 mL/min, -23.91 to -2.80) and 2 years (2 studies: MD -12.86 mL/min, -23.73 to -2.00) compared to ATG plus triple maintenance. Across all 6 studies, the effect of alemtuzumab versus ATG was uncertain on all-cause infection, CMV infection, BK virus infection, malignancy, and PTLD. The effect of alemtuzumab with steroid minimisation on NODAT was uncertain, compared to ATG with steroid maintenance.Alemtuzumab plus ESW compared with triple maintenance without induction therapy had uncertain effects on death and all-cause graft loss at 1 year, acute rejection at 6 months and 1 year. CMV infection was increased (2 studies: RR 2.28, 1.18 to 4.40). Treatment effects were uncertain for NODAT, thrombocytopenia, and malignancy or PTLD.Rituximab had uncertain effects on death, graft loss, acute rejection and all other adverse outcomes compared to placebo.
AUTHORS' CONCLUSIONS
ATG reduces acute rejection but has uncertain effects on death, graft survival, malignancy and NODAT, and increases CMV infection, thrombocytopenia and leucopenia. Given a 45% acute rejection risk without ATG induction, seven patients would need treatment to prevent one having rejection, while incurring an additional patient experiencing CMV disease for every 12 treated. Excluding non-CNI studies, the risk of rejection was 37% without induction with six patients needing treatment to prevent one having rejection.In the context of steroid minimisation, alemtuzumab prevents acute rejection at 1 year compared to ATG. Eleven patients would require treatment with alemtuzumab to prevent 1 having rejection, assuming a 21% rejection risk with ATG.Triple maintenance without induction therapy compared to alemtuzumab combined with ESW had similar rates of acute rejection but adverse effects including NODAT were poorly documented. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple maintenance, in the absence of any clinical benefit. Overall, ATG and alemtuzumab decrease acute rejection at a cost of increased CMV disease while patient-centred outcomes (reduced death or lower toxicity) do not appear to be improved.
Topics: Acute Disease; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Calcineurin Inhibitors; Cytomegalovirus Infections; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Randomized Controlled Trials as Topic; Receptors, Interleukin-2; Steroids
PubMed: 28073178
DOI: 10.1002/14651858.CD004759.pub2 -
The Cochrane Database of Systematic... Jul 2013Acquired severe aplastic anemia is a rare and potentially fatal disease, which is characterized by hypocellular bone marrow and pancytopenia. The major signs and... (Meta-Analysis)
Meta-Analysis Review
First-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared with first-line ciclosporin and/or antithymocyte or antilymphocyte globulin for acquired severe aplastic anemia.
BACKGROUND
Acquired severe aplastic anemia is a rare and potentially fatal disease, which is characterized by hypocellular bone marrow and pancytopenia. The major signs and symptoms are severe infections, bleeding, and exhaustion. First-line allogeneic hematopoietic stem cell transplantation (HSCT) of a human leukocyte antigen (HLA)-matched sibling donor (MSD) is a treatment for newly diagnosed patients with severe aplastic anemia. First-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin (as first-line immunosuppressive therapy) is an alternative to MSD-HSCT and is indicated for patients where no MSD is found.
OBJECTIVES
To evaluate the effectiveness and adverse events of first-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared to first-line immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin in patients with acquired severe aplastic anemia.
SEARCH METHODS
We searched the electronic databases MEDLINE (Ovid), EMBASE (Ovid), and The Cochrane Library CENTRAL (Wiley) for published articles from 1946 to 22 April 2013. Further searches included trial registries, reference lists of recent reviews, and author contacts.
SELECTION CRITERIA
The following prospective study designs were eligible for inclusion: randomized controlled trials (RCTs) and non-randomized controlled trials if the allocation of patients to treatment groups was consistent with 'Mendelian randomization'. We included participants with newly diagnosed severe aplastic anemia who received MSD-HSCT or immunosuppressive therapy without prior HSCT or immunosuppressive therapy, and with a minimum of five participants per treatment group. We did not apply limits on publication year or languages.
DATA COLLECTION AND ANALYSIS
Two review authors abstracted the data on study and patient characteristics and assessed the risk of bias independently. We resolved differences by discussion or by appeal to a third review author. The primary outcome was overall mortality. Secondary outcomes were treatment-related mortality, graft failure, no response to first-line immunosuppressive therapy, graft-versus-host-disease (GVHD), relapse after initial successful treatment, secondary clonal and malignant disease, health-related quality of life, and performance score.
MAIN RESULTS
We identified three trials that met the inclusion criteria. None of these trials was a RCT. 302 participants are included in this review. The three included studies were prospectively conducted and had features consistent with the principle of 'Mendelian randomization' as defined in the present review. All studies had a high risk of bias due to the study design. All studies were conducted more than 10 years ago and may not be applicable to the standard of care of today. Primary and secondary outcome data showed no statistically significant difference between treatment groups. We present results for first-line allogeneic hematopoietic stem cell transplantation of an HLA-matched sibling donor, which we denote as the MSD-HSCT group, versus first-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin, which we denote as the immunosuppressive therapy group in the following section.The pooled hazard ratio for overall mortality for the MSD-HSCT group versus the immunosuppressive therapy group was 0.95 (95% confidence interval 0.43 to 2.12, P = 0.90, low quality evidence). Therefore, overall mortality was not statistically significantly different between the groups. Treatment-related mortality ranged from 20% to 42% for the MSD-HSCT group and was not reported for the immunosuppressive therapy group (very low quality evidence). The authors reported graft failure from 3% to 16% for the MSD-HSCT group and GVHD from 26% to 51% (both endpoints not applicable for the immunosuppressive therapy group, very low quality evidence). The authors did not report any data on response and relapse for the MSD-HSCT group. For the immunosuppressive therapy group, the studies reported no response from 15% (not time point stated) to 64% (three months) and relapse in one of eight responders after immunosuppressive therapy at 5.5 years (very low quality evidence). The authors reported secondary clonal disease or malignancies for the MSD-HSCT group versus the immunosuppressive therapy group in 1 of 34 versus 0 of 22 patients in one study and in 0 of 28 versus 4 of 86 patients in the other study (low quality evidence). None of the included studies addressed health-related quality of life. The percentage of the evaluated patients with a Karnofsky performance status score in the range of 71% to 100% was 92% in the MSD-HSCT group and 46% in the immunosuppressive therapy group.
AUTHORS' CONCLUSIONS
There are insufficient and biased data that do not allow any conclusions to be made about the comparative effectiveness of first-line allogeneic hematopoietic stem cell transplantation of an HLA-matched sibling donor and first-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin (as first-line immunosuppressive therapy). We are unable to make firm recommendations regarding the choice of intervention for treatment of acquired severe aplastic anemia.
Topics: Anemia, Aplastic; Antilymphocyte Serum; Cyclosporine; Graft Rejection; Graft vs Host Disease; HLA Antigens; Hematopoietic Stem Cell Transplantation; Histocompatibility; Humans; Immunosuppressive Agents; Mendelian Randomization Analysis; Siblings; T-Lymphocytes; Transplantation, Homologous
PubMed: 23881658
DOI: 10.1002/14651858.CD006407.pub2 -
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 -
Haematologica Jan 2020Immunosuppressive therapy (IST) is one therapy option for treatment of patients with lower-risk myelodysplastic syndromes (MDS). However, the use of several different... (Meta-Analysis)
Meta-Analysis
Immunosuppressive therapy (IST) is one therapy option for treatment of patients with lower-risk myelodysplastic syndromes (MDS). However, the use of several different immunosuppressive regimens, the lack of high-quality studies, and the absence of validated predictive biomarkers pose important challenges. We conducted a systematic review and meta-analysis according to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and searched MEDLINE PubMed, Ovid EMBASE, COCHRANE registry of clinical trials (CENTRAL), and the Web of Science without language restriction from inception through September 2018, as well as relevant conference proceedings and abstracts, for prospective cohort studies or clinical trials investigating IST in MDS. Fixed and Random-effects models were used to pool response rates. We identified nine prospective cohort studies and 13 clinical trials with a total of 570 patients. Overall response rate was 42.5% [95% confidence interval (CI): 36.1-49.2%] including a complete remission rate of 12.5% (95%CI: 9.3-16.6%) and red blood cell transfusion independence rate of 33.4% (95% CI: 25.1-42.9%). The most commonly used forms of IST were anti-thymocyte globulin alone or in combination with cyclosporin A with a trend towards higher response rates with combination therapy. Progression rate to acute myeloid leukemia was 8.6% per patient year (95%CI: 3.3-13.9%). Overall survival and adverse events were only inconsistently reported. We were unable to validate any biomarkers predictive of a therapeutic response to IST. IST for treatment of lower-risk MDS patients can be successful to alleviate transfusion burden and associated sequelae.
Topics: Antilymphocyte Serum; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Myelodysplastic Syndromes; Prospective Studies
PubMed: 31004015
DOI: 10.3324/haematol.2019.219345 -
The Cochrane Database of Systematic... Jul 2017Registry data shows that the incidence of acute rejection has been steadily falling. Approximately 10% to 35% of kidney recipients will undergo treatment for at least... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Registry data shows that the incidence of acute rejection has been steadily falling. Approximately 10% to 35% of 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. Over recent years, new treatment strategies have evolved, and in many parts of the world there has been an increase in use of tacrolimus and mycophenolate and a reduction in the use of cyclosporin and azathioprine use as baseline immunosuppression to prevent acute rejection. There are also global variations in use of polyclonal and monoclonal antibodies to treat acute rejection. This is an update of a review published in 2006.
OBJECTIVES
The aim of this systematic review was to: (1) to evaluate the relative and absolute effects of different classes of antibody preparation in preventing graft loss and resolving cellular or humoral rejection episodes when used as a treatment for first episode of rejection in kidney transplant recipients; (2) evaluate the relative and absolute effects of different classes of antibody preparation in preventing graft loss and resolving cellular or humoral rejection episodes when used as a treatment for steroid-resistant rejection in kidney transplant recipients; (3) determine how the benefits and adverse events vary for each type of antibody preparation; and (4) determine how the benefits and harms vary for different formulations of antibody within each type.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Specialised Register to 18 April 2017 through contact with the Information Specialist using search terms relevant to this review.
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 cellular or humoral graft rejection, when compared to any other treatment for acute rejection were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed the risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).
MAIN RESULTS
We included 11 new studies (18 reports, 346 participants) in this update, bring the total number of included studies to 31 (76 reports, 1680 participants). Studies were generally small, incompletely reported, especially for potential harms, and did not define outcome measures adequately. The risk of bias was inadequate or unclear risk for random sequence generation (81%), allocation concealment (87%) and other bias (87%). There were, however, a predominance of low risk of bias for blinding (75%) and incomplete outcome data (80%) across all the studies. Selective reporting had a mixture of low (58%), high (29%), and unclear (13%) risk of bias.Seventeen studies (1005 participants) compared therapies for first acute cellular rejection episodes. Antibody therapy was probably better than steroid in reversing acute cellular rejection (RR 0.50, 95% CI 0.30 to 0.82; moderate certainty) and preventing subsequent rejection (RR 0.70, 95% CI 0.50 to 0.99; moderate certainty), may be better for preventing graft loss (death censored: (RR 0.80, 95% CI 0.57 to 1.12; low certainty) but there was little or no difference in death at one year. Adverse effects of treatment (including fever, chills and malaise following drug administration) were probably reduced with steroid therapy (RR 23.88, 95% CI 5.10 to 111.86; I = 16%; moderate certainty).Twelve studies (576 patients) investigated antibody treatment for steroid-resistant rejection. There was little or no benefit of muromonab-CD3 over ATG or ALG in reversing rejection, preventing subsequent rejection, or preventing graft loss or death. Two studies compared the use of rituximab for treatment of acute humoral rejection (58 patients). Muromonab-CD3 treated patients suffered three times more than those receiving either ATG or T10B9, from a syndrome of fever, chills and malaise following drug administration (RR 3.12, 95% CI 1.87 to 5.21; I = 31%), and experienced more neurological side effects (RR 13.10 95% CI 1.43 to 120.05; I = 36%) (low certainty evidence).There was no evidence of additional benefit from rituximab in terms of either reversal of rejection (RR 0.94, 95% CI 0.54 to 1.64), or graft loss or death 12 months (RR 1.0, 95% CI 0.23 to 4.35). Rituximab plus steroids probably increases the risk of urinary tract infection/pyelonephritis (RR 5.73, 95% CI 1.80 to 18.21).
AUTHORS' CONCLUSIONS
In reversing first acute cellular rejection and preventing graft loss, any antibody is probably better than steroid, but there is little or no difference in subsequent rejection and patient survival. In reversing steroid-resistant rejection there was little or no difference between different antibodies over a period of 12 months, with limited data beyond that time frame. In treating acute humoral rejection, there was no evidence that the use of antibody therapy conferred additional benefit in terms of reversal of rejection, or death or graft loss.Although this is an updated review, the majority of newer included studies provide additional evidence from the cyclosporin/azathioprine era of kidney transplantation and therefore conclusions cannot necessarily be extrapolated to patients treated with more contemporary immunosuppressive regimens which include tacrolimus/mycophenolate or sirolimus. However, many kidney transplant centres around the world continue to use older immunosuppressive regimes and the findings of this review remain strongly relevant to their clinical practice.Larger studies with standardised reproducible outcome criteria are needed to investigate the outcomes and risks of antibody treatments for acute rejection in kidney transplant recipients receiving contemporary immunosuppressive regimes.
Topics: Acute Disease; Antibodies; Antibodies, Monoclonal; Antilymphocyte Serum; Drug Resistance; Graft Rejection; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Randomized Controlled Trials as Topic; Rituximab
PubMed: 28731207
DOI: 10.1002/14651858.CD004756.pub4 -
Bone Marrow Transplantation Jul 2019Graft-versus-host disease (GVHD) remains a limiting factor for successful allogeneic hematopoietic cell transplantation (allo-HCT). Conflicting data exist on the benefit... (Meta-Analysis)
Meta-Analysis
Graft-versus-host disease (GVHD) remains a limiting factor for successful allogeneic hematopoietic cell transplantation (allo-HCT). Conflicting data exist on the benefit of ATG on post-transplant survival. We performed a systematic review of randomized controlled trials (RCTs) to assess benefits and harms of thymoglobulin and Fresenius (re-branded as Grafalon) ATG formulations in patients undergoing allo-HCT for a variety of hematologic malignancies and bone marrow failure syndromes. A comprehensive search of MEDLINE, EMBASE, and Cochrane Library was performed. Data on methodological quality, benefits, and harms were extracted for each trial and pooled under a random-effects model. Eight RCTs (1134 patients) met the inclusion criteria. Methodological quality ranged from moderate to very low. Pooled results showed no difference in overall survival (OS) with the use of ATG (hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.74-1.28; P = 0.83). ATG reduced grade II/III acute GVHD (risk ratio (RR) = 0.61; 95% CI = 0.48-0.77; P < 0.0001), grade III/IV acute GVHD (RR = 0.52; 95% CI = 0.34-0.81; P = 0.004), and chronic GVHD (RR = 0.52; 95% CI = 0.40-0.69; P < 0.00001) without an increase in non-relapse mortality (NRM) (RR = 0.91; 95% CI = 0.74-1.13; P = 0.40). Future studies with better methodological quality are needed to provide conclusive answers related to optimal dosing and timing of ATG for prevention of GVHD.
Topics: Acute Disease; Allografts; Antilymphocyte Serum; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; MEDLINE; Male; Randomized Controlled Trials as Topic; Survival Rate
PubMed: 30446739
DOI: 10.1038/s41409-018-0393-0