Comparison between horse and rabbit antithymocyte globulin as first-line treatment for patients with severe aplastic anemia: a single-center retrospective study

The best antithymocyte globulin preparation for first-line immune suppression in patients with severe aplastic anemia is still not clear. The aim of this study was to compare hematological response and overall survival in patients submitted to horse or rabbit antithymocyte globulin as first-line treatment for severe aplastic anemia. We retrospectively compared 71 consecutive patients with severe aplastic anemia, classified according to the antithymocyte globulin preparation. Analyses included variables related to patients and to immune suppression. Forty two patients (59.1%) received horse and 29 (40.9%) rabbit antithymocyte globulin. Response rates were higher at 6 months in patients submitted to horse in comparison to rabbit antithymocyte globulin (59.5% versus 34.5% respectively, p = 0.05). Median time to response was similar between the two groups (99 versus 88.5 days, respectively, for horse and rabbit antithymocyte globulin; p = 0.98). Overall survival at 2 years was significantly higher in patients submitted to horse in comparison to rabbit antithymocyte globulin (78.4% versus 55.4%, p = 0.03). Post-treatment response was strongly associated with survival at 2 years (97% in responders versus 41.2% in non-responders, p < 0.001). Use of rabbit antithymocyte globulin was an independent predictor of death (odds ratio 2.5; 95% confidence interval 1.03–6.04; p = 0.04). Rabbit antithymocyte globulin was associated with a significant and prolonged lymphopenia in comparison with horse antithymocyte globulin. Our data suggest the superiority of horse over rabbit antithymocyte globulin as first-line treatment for severe aplastic anemia, both regarding hematological response and survival.     

Predictors of early mortality after rabbit antithymocyte globulin as first-line treatment in severe aplastic anemia

Despite being recommended as first-line immunosuppressive therapy in severe aplastic anemia (SAA), horse antithymocyte globulin (ATG) is still unavailable in many countries outside the USA. Rabbit ATG is more lymphocytoxic than horse ATG, and this might result in a higher incidence of severe infections and early mortality. This study was designed to identify the risk factors for early mortality and overall survival (OS) after rabbit ATG in patients with SAA. We retrospectively reviewed 185 patients with SAA who underwent rabbit ATG and cyclosporine. The incidence of death in 3 months following rabbit ATG therapy was 15.1% (28/185). Early mortality was mainly related to infectious complications, despite adequate antibiotic and/or antifungal treatment. Age > 35 years (odds ratio [OR] 5.06, P = 0.001) and baseline absolute neutrophil count (ANC) ≤ 0.1 × 10⁹/L (OR 7.64, P < 0.001) were independent risk factors for early mortality after immunosuppressive therapy with this agent. Hematological response at 6 months was observed in only 29.7% of all patients. OS at 1 year after rabbit ATG was 75.3%; and age > 35 years (OR 1.88, P = 0.03), baseline ANC ≤ 0.1 × 10⁹/L (OR 2.65, P < 0.001), and lack of response to rabbit ATG (OR 11.40, P < 0.001) were independently associated with mortality. Alternative strategies are needed for the treatment of SAA patients in countries were horse ATG is unavailable, particularly for those at high risk for early mortality after rabbit ATG due to a higher age and very low pre-treatment neutrophil count.     

猪抗人淋巴细胞球蛋白治疗重型再生障碍性贫血的临床研究

目的：探讨一线应用猪抗人淋巴细胞球蛋白（P-ALG）联合环孢素（CsA）治疗重型再生障碍性贫血（SAA）的疗效及不良反应。方法回顾性分析我科应用 P-ALG 联合 CsA 治疗36例 SAA 患者的疗效、并发症及转归,并对患者的年龄、疾病严重程度、发病距应用 P-ALG 的时间等因素与疗效进行相关分析。结果36例患者中死亡4例,白细胞恢复中位时间为30天,脱离红细胞输注的中位时间为55天,脱离血小板输注的中位时间为60天。1年总有效率为86．2％,2年总有效率达91．7％,1年总有效率与性别、年龄、疾病分型、CD8比例无明显相关（P ＞0．05）,病程＜3个月及外周血中性粒细胞（ANC）≥0．2×109／L 患者的有效率高;与国内及欧美国家报道的利用马或兔抗胸腺细胞球蛋白（ATG）治疗 SAA 的有效率相当,而不良反应小,花费仅为马或兔 ATG 治疗的1／3～1／2。结论应用 P-ALG 联合 CsA 治疗重型再生障碍性贫血疗效显著,不良反应轻微。     

In vivo effects of horse and rabbit antithymocyte globulin in patients with severe aplastic anemia

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: {"type":"clinical-trial","attrs":{"text":"NCT00260689","term_id":"NCT00260689"}}NCT00260689.     

Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia

Immunosuppressive therapy can produce hematologic improvement in a large proportion of patients with severe aplastic anemia. Antithymocyte globulin (ATG) is the current treatment of choice for patients who do not have histocompatible sibling donors or who are otherwise inegligible for allogeneic bone marrow transplantation. About 50% of patients respond to an initial course of ATG, and many nonresponders can be salvaged by subsequent treatment with cyclosporine (CsA). To determine whether simultaneous administration of these agents could further improve response rates, we enrolled 55 patients in a therapeutic trial of 4 days of ATG and 6 months of CsA. Among the 51 patients who had not received previous courses of ATG or CsA, 67% had responded by 3 months, and 78% had responded by 1 year (response was defined as an increase in peripheral blood counts sufficient that a patient no longer met the criteria for severe disease). There was a high incidence of relapse (36% actuarial risk at 2 years), but most relapsed patients responded to additional courses of immunosuppression, and relapse was not associated with a significant survival disadvantage. Evolution to myelodysplastic syndromes and acute leukemia was rare (1 of 51 patients), but the later appearance of paroxysmal nocturnal hemoglobinuria was more common (5 of 51 patients). Actuarial survival was 86% at 1 year and 72% at 2 years. These data support the use of a combination immunosuppressive regimen containing both ATG and CsA as first-line therapy for severe aplastic anemia.     

Horse antithymocyte globulin as salvage therapy after rabbit antithymocyte globulin for severe aplastic anemia

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. Am. J. Hematol. 89:467–469, 2014. © Published 2014.     

Long-term outcome after immunosuppressive therapy with horse or rabbit antithymocyte globulin and cyclosporine for severe aplastic anemia in children

Some prospective studies showed that rabbit antithymocyte globulin was inferior to horse antithymocyte globulin as first-line therapy for patients with severe aplastic anemia. We retrospectively analyzed the clinical outcome of 455 children with severe aplastic anemia who received horse antithymocyte globulin (n=297) or rabbit antithymocyte globulin (n=158) combined with cyclosporine as first-line therapy between 1992 and 2010. The response rates were comparable between the horse and rabbit antithymocyte globulin groups at 3 months [46% (136/294) versus 42% (66/153), P=0.55] and 6 months [60% (178/292) versus 55% (87/143), P=1.0]. Using multivariate analysis, differences in antithymocyte globulin preparations were not associated with response rates. However, 2-year and 10-year overall survival rates in the horse antithymocyte globulin group were significantly better than those in the rabbit antithymocyte globulin group (2-year overall survival: 96% versus 87%, 10-year overall survival: 92% versus 84%, P=0.004). On the basis of multivariate analysis, use of rabbit antithymocyte globulin was a significant adverse factor for overall survival (hazard ratio = 3.56, 95% confidence interval, 1.53 – 8.28, P=0.003). Rabbit antithymocyte globulin caused more profound immunosuppression, which might be responsible for the higher incidence of severe infections. Considering that there are no studies showing the superiority of rabbit antithymocyte globulin over horse antithymocyte globulin, horse antithymocyte globulin should be recommended as a first-line therapy. However, our results justify the use of rabbit antithymocyte globulin as first-line therapy if horse antithymocyte globulin is not available.     

Immunosuppressive treatment of aplastic anemia with antithymocyte globulin and cyclosporine

Immunosuppression is the treatment modality for the majority of patients with aplastic anemia, most of whom are not candidates for allogeneic stem-cell transplantation. Antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) have proven to be essential components of all regimens. Initial response rates can be improved by the addition of cyclosporine A (CsA), and this combination has become the standard of care for appropriate patients. Several new approaches to immunosuppression are being studied, including the optimal timing of administration of these drugs, the use of novel immunosuppressive agents, and the addition of early- and late-acting hematopoietic growth factors.     

Paroxysmal nocturnal hemoglobinuria clones in severe aplastic anemia patients treated with horse anti-thymocyte globulin plus cyclosporine

Background

Clones of glycosylphosphatidylinositol-anchor protein-deficient cells are characteristic in paroxysmal nocturnal hemoglobinuria and are present in about 40–50% of patients with severe aplastic anemia. Flow cytometry has allowed for sensitive and precise measurement of glycosylphosphatidylinositol-anchor protein-deficient red blood cells and neutrophils in severe aplastic anemia.

Design and Methods

We conducted a retrospective analysis of paroxysmal nocturnal hemoglobinuria clones measured by flow cytometry in 207 consecutive severe aplastic anemia patients who received immunosuppressive therapy with a horse anti-thymocyte globulin plus cyclosporine regimen from 2000 to 2008.

Results

The presence of a glycosylphosphatidylinositol-anchor protein-deficient clone was detected in 83 (40%) patients pre-treatment, and the median clone size was 9.7% (interquartile range 3.5–29). In patients without a detectable clone pre-treatment, the appearance of a clone after immunosuppressive therapy was infrequent, and in most with a clone pre-treatment, clone size often decreased after immunosuppressive therapy. However, in 30 patients, an increase in clone size was observed after immunosuppressive therapy. The majority of patients with a paroxysmal nocturnal hemoglobinuria clone detected after immunosuppressive therapy did not have an elevated lactate dehydrogenase, nor did they experience hemolysis or thrombosis, and they did not require specific interventions with anticoagulation and/or eculizumab. Of the 7 patients who did require therapy for clinical paroxysmal nocturnal hemoglobinuria symptoms and signs, all had an elevated lactate dehydrogenase and a clone size greater than 50%. In all, 18 (8.6%) patients had a clone greater than 50% at any given time of sampling.

Conclusions

The presence of a paroxysmal nocturnal hemoglobinuria clone in severe aplastic anemia is associated with low morbidity and mortality, and specific measures to address clinical paroxysmal nocturnal hemoglobinuria are seldom required.     

Immunosuppressive therapy with horse anti-thymocyte globulin and cyclosporine as treatment for fulminant aplastic anemia in children

Patients with severe aplastic anemia (SAA) and an absolute neutrophil count (ANC) of 0 typically have fatal outcomes. We defined fulminant AA (FAA) as ANC?=?0 for at least 2 weeks prior to and after immunosuppressive therapy (IST). We analyzed the outcomes of 35 children with FAA among 288 children who enrolled in a prospective study for AA (AA-97 study). AA was classified as FAA (n?=?35), very SAA (vSAA; n?=?129), or SAA (n?=?124). All of the children received the IST with horse anti-thymocyte globulin (ATG) and cyclosporine (CsA). A significantly lower response rate at 6 months was seen in children with FAA when compared to those with vSAA or SAA (40.0, 63.6, and 63.7 %, respectively; p?=?0.027). Of 20 nonresponder patients in the FAA group, 11 were rescued by alternative donor transplantation, and 5 patients showed a late response after 6 months. Consequently, no significant difference was noted in overall survival when comparing the FAA, vSAA, and SAA groups (88.5, 95.8, and 96.8 %). These findings indicate that IST with ATG and CsA is justified as a first-line treatment for children with FAA who lack a human leukocyte antigen-matched sibling donor.