Antithymocyte globulin and cyclosporin: standard of care also for older patients with aplastic anemia.
Ontology highlight
ABSTRACT:
SUBMITTER: Bacigalupo A
PROVIDER: S-EPMC6355485 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
Publications
Antithymocyte globulin and cyclosporin: standard of care also for older patients with aplastic anemia.
Haematologica 20190201 2
Similar Datasets
Project description: Not available
| S-EPMC5566012 | biostudies-literature
Project description:The effectiveness of salvage therapy for aplastic anemia patients unresponsive to initial rabbit antithymocyte globulin (r-ATG) or cyclophosphamide is not known. We investigated the administration of standard horse ATG (h-ATG) plus cyclosporine (CsA) in patients who were refractory to initial r-ATG/CsA (n = 19) or cyclophosphamide/CsA (n = 6) (registered at clinicaltrials.gov as NCT00944749). The primary endpoint was hematologic response at 3 months and was defined as no longer meeting the criteria for severe aplastic anemia. Of the 19 patients who received r-ATG as initial therapy, 4 (21%) achieved a hematologic response by 3 months, and of the 6 patients who received cyclophosphamide, only 1 (17%) responded by 6 months. Among the responders there were no cases of relapse, and in nonresponders 2 patients evolved to monosomy 7. The overall survival for the cohort at 3 years was 68% (95% CI, 50-91%). These results suggest that only a minority can be successfully salvaged after receiving as first therapy either r-ATG or cyclophosphamide. Although h-ATG may be utilized in the salvage setting, the overall response rate probably will be lower than when h-ATG is used as initial treatment.
| S-EPMC4058301 | biostudies-literature
Project description:BACKGROUND:In severe acquired aplastic anemia, hematopoietic failure is the result of immune-mediated destruction of bone marrow stem and progenitor cells. Immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporine is an effective alternative to stem-cell transplantation and improves blood counts and survival. Although horse ATG is the standard therapy, rabbit ATG is more potent in depleting peripheral-blood lymphocytes and is preferred in other clinical circumstances. METHODS:From December 2005 through July 2010, we performed a randomized trial comparing these two ATG formulations in conventional regimens. Patients were treated at a single facility. The primary outcome was hematologic response at 6 months, as determined by blood counts. The study was designed to enroll 60 patients each for the rabbit-ATG and horse-ATG groups and was powered to detect a difference of 25 percentage points in the response rate. RESULTS:A large, unexpected difference was observed in the rate of hematologic response at 6 months in favor of horse ATG (68%; 95% confidence interval [CI], 56 to 80) as compared with rabbit ATG (37%; 95% CI, 24 to 49; P<0.001). Overall survival at 3 years also differed, with a survival rate of 96% (95% CI, 90 to 100) in the horse-ATG group as compared with 76% (95% CI, 61 to 95) in the rabbit-ATG group (P=0.04) when data were censored at the time of stem-cell transplantation, and 94% (95% CI, 88 to 100) as compared with 70% (95% CI, 56 to 86; P=0.008) in the respective groups when stem-cell-transplantation events were not censored. CONCLUSIONS:In a randomized study, rabbit ATG was inferior to horse ATG as a first treatment for severe aplastic anemia, as indicated by hematologic response and survival. (Funded by the Intramural Research Program of the National Institutes of Health; ClinicalTrials.gov number, NCT00260689.).
| S-EPMC3721503 | biostudies-literature
Project description:We recently reported that rabbit antithymocyte globulin was markedly inferior to horse antithymocyte globulin as a primary treatment for severe aplastic anemia. Here we expand on our findings in this unique cohort of patients. Rabbit antithymocyte globulin was detectable in plasma for longer periods than horse antithymocyte globulin; rabbit antithymocyte globulin in plasma retained functional capacity to bind to lymphocytes for up to 1 month, horse antithymocyte globulin for only about 2 weeks. In the first week after treatment there were much lower numbers of neutrophils in patients treated with rabbit antithymocyte globulin than in patients receiving horse antithymocyte globulin. Both antithymocyte globulins induced a "cytokine storm" in the first 2 days after administration. Compared with horse antithymocyte globulin, rabbit antithymocyte globulin was associated with higher levels of chemokine (C-C motif) ligand 4 during the first 3 weeks. Besides a much lower absolute number and a lower relative frequency of CD4(+) T cells, rabbit antithymocyte globulin induced higher frequencies of CD4(+)CD38(+), CD3(+)CD4(-)CD8(-) T cells, and B cells than did horse antithymocyte globulin. Serum sickness occurred around 2 weeks after infusion of both types of antithymocyte globulin. Human anti-antithymocyte globulin antibodies, especially of the IgM subtype, correlated with serum sickness, which appeared concurrently with clearance of antithymocyte globulin in blood and with the production of cytokines. In conclusion, rabbit and horse antithymocyte globulins have very different pharmacokinetics and effects on neutrophils, lymphocyte subsets, and cytokine release. These differences may be related to their efficacy in suppressing the immune system and restoring hematopoiesis in bone marrow failure. Clinicaltrials.gov identifier: NCT00260689.
| S-EPMC4562531 | biostudies-literature
Project description:For treatment of severe aplastic anemia, immunosuppressive therapy with horse antithymocyte globulin results in superior response and survival compared with rabbit antithymocyte globulin. This relative benefit may be different in the setting of transplantation as rabbit antithymocyte globulin results in more profound immunosuppression. We analyzed 833 severe aplastic anemia transplants between 2008 and 2013 using human leukocyte antigen (HLA)-matched siblings (n=546) or unrelated donors (n=287) who received antithymocyte globulin as part of their conditioning regimen and bone marrow graft. There were no differences in hematopoietic recovery by type of antithymocyte globulin. Among recipients of HLA-matched sibling transplants, day 100 incidence of acute (17% versus 6%, P<0.001) and chronic (20% versus 9%, P<0.001) graft-versus-host disease were higher with horse compared to rabbit antithymocyte globulin. There were no differences in 3-year overall survival, 87% and 92%, P=0.76, respectively. Among recipients of unrelated donor transplants, acute graft-versus-host disease was also higher with horse compared to rabbit antithymocyte globulin (42% versus 23%, P<0.001) but not chronic graft-versus-host disease (38% versus 32%, P=0.35). Survival was lower with horse antithymocyte globulin after unrelated donor transplantation, 75% versus 83%, P=0.02. These data support the use of rabbit antithymocyte globulin for bone marrow transplant conditioning for severe aplastic anemia.
| S-EPMC5566045 | biostudies-literature
Project description:Aplastic anemia (AA) is frequently caused by a T-cell mediated autoimmune depletion of the hematopoietic stem and progenitor cell (HSPC) compartment. Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine represents the first-line treatment of AA. One side effect of ATG therapy is the release of proinflammatory cytokines such as interferon-gamma (IFN-γ), which is considered a major factor in the pathogenic autoimmune depletion of HSPC. Recently, eltrombopag (EPAG) was introduced for therapy of refractory AA patients due to its ability to bypass IFN-γ-mediated HSPC inhibition among other mechanisms. Clinical trials have evidenced that EPAG started simultaneously with IST leads to a higher response rate compared with its later administration schedules. We hypothesize that EPAG might protect HSPC from negative effects of ATG-induced release of cytokines. We observed a significant decrease in colony numbers when both healthy peripheral blood (PB) CD34+ cells and AA-derived bone marrow cells were cultured in the presence of serum from patients under ATG treatment, as compared with before treatment. Consistent with our hypothesis, this effect could be rescued by adding EPAG in vitro to both healthy and AA-derived cells. By employing an IFN-γ neutralizing antibody, we also demonstrated that the deleterious early ATG effects on the healthy PB CD34+ compartment were mediated at least partially by IFN-γ. Hence, we provide evidence for the hitherto unexplained clinical observation that concomitant use of EPAG in addition to IST comprising ATG leads to improved response in patients with AA.
| S-EPMC10249716 | biostudies-literature
Project description:In severe aplastic anemia, approximately one-third of responders to standard horse antithymocyte globulin (h-ATG) plus cyclosporine (CsA) will relapse. Anecdotal experience has suggested that a gradual CsA taper might avoid relapse, but this practice has not been rigorously assessed prospectively. In 2003, we adopted a strategy to taper CsA beyond 6 months, with the intention to reduce hematologic relapse compared with our extensive historical experience. In total, 102 patients received h-ATG/CsA for 6 months in two sequential clinical protocols: 67 patients (66%) responded and all had the CsA dose tapered per protocol over the subsequent 18 months (total of 2 years). The rate of relapse at 5 years was 33% (95% CI 27-44%), which did not differ from our large historical relapse experience (patients treated before 2003) of 30-40%, in protocols in which CsA was simply discontinued at 6 months. However, time to relapse was prolonged by about 1 year with the longer CsA course. The rates of clonal evolution and overall survival did not differ between the two cohorts. We infer from this large prospective study that CsA taper as implemented delayed but did not prevent relapse. The kinetics of relapse with long course CsA does suggest that a lower long-term dose might be adequate to maintain patients in remission.
| S-EPMC4074770 | biostudies-literature
Project description: Not available
| S-EPMC4238067 | biostudies-literature
Project description: Not available
| S-EPMC10428470 | biostudies-literature
Project description:BackgroundWe hypothesized that the addition of sirolimus to standard horse antithymocyte globulin (h-ATG) and cyclosporine (CsA) would improve response rates in severe aplastic anemia, due to its complementary and synergistic properties to cyclosporine A.Design and methodsTo test this hypothesis, we conducted a prospective randomized study comparing hATG/CsA/sirolimus to standard h-ATG/CsA. A total of 77 patients were treated from June 2003 to November 2005; 35 received h-ATG/CsA/sirolimus and 42 h-ATG/CsA. The two groups were well matched demographically and in blood counts prior to therapy. The primary end-point was hematologic response rate at 3 months, defined as no longer meeting the criteria for severe aplastic anemia. The study was powered to show a superior hematologic response rate of h-ATG/CsA/sirolimus compared to standard h-ATG/CsA.ResultsThe overall response rate at 3 months was 37% for h-ATG/CsA/sirolimus and 50% for h-ATG/CsA and at 6 months 51% for h-ATG/CsA/sirolimus and 62% for h-ATG/CsA. After a planned interim analysis of 30 evaluable patients in each arm, accrual to the h-ATG/CsA/sirolimus arm was closed, as the conditional power for rejecting the null hypothesis was less than 1%. The rate of relapse, clonal evolution, and survival (secondary outcomes) did not differ significantly between patients treated with the two different regimens.ConclusionsDespite a theoretical rationale for its use, sirolimus did not improve the response rate in patients with severe aplastic anemia when compared to standard h-ATG/CsA.
| S-EPMC2649367 | biostudies-literature