Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party

Abstract

Rabbit antithymocyte globulin (rATG; thymoglobulin, Genzyme) in combination with cyclosporine, as first-line immunosuppressive therapy, was evaluated prospectively in a multicenter, European, phase 2 pilot study, in 35 patients with aplastic anemia. Results were compared with 105 age-and disease severitymatched patients from the European Blood and Marrow Transplant registry, treated with horse ATG (hATG; lymphoglobulin) and cyclosporine. The primary end point was response at 6 months. At 3 months, no patients had achieved a complete response to rATG. Partial response occurred in 11 (34%). At 6 months, complete response rate was 3% and partial response rate 37%. There were 10 deaths after rATG (28.5%) and 1 after subsequent HSCT. Infections were the main cause of death in 9 of 10 patients. The best response rate was 60% for rATG and 67% for hATG. For rATG, overall survival at 2 years was 68%, compared with 86% for hATG (P ‫؍‬ .009). Transplant-free survival was 52% for rATG and 76% for hATG (P ‫؍‬ .002). On multivariate analysis, rATG (hazard ratio ‫؍‬ 3.9, P ‫؍‬ .003) and age more than 37 years (hazard ratio ‫؍‬ 4.7, P ‫؍‬ .0008) were independent adverse risk factors for survival. This study was registered at www.clinicaltrials.gov as NCT00471848. (Blood. 2012;119(23): 5391-5396) IntroductionHistorically, horse antithymocyte globulin (hATG) has been the preferred animal source of ATG as first-line treatment for acquired aplastic anemia (AA) patients who are ineligible for hematopoietic stem cell transplantation (HSCT). For severe AA (SAA), the combination of ATG and cyclosporine (CSA) results in a response rate of 60% to 75% of patients, and the response is superior to using either agent alone. [1][2][3][4][5] The addition of G-CSF to the combination of ATG and CSA has shown no significant benefit either in terms of response or survival, 6-8 although it may reduce infectious complications and duration of hospital admission. 6 For patients with nonsevere AA (NSAA) who are transfusion dependent, the combination of ATG and CSA is superior to CSA alone, with a higher response rate, higher blood counts, and improved disease-free survival. 9 Rabbit ATG (rATG) is more commonly used for a second course after relapse or lack of response to a first course of hATG. Response to a second course for nonresponse to a first course varies from 30% to 77% 10,11 and only 11% in children. 12 In contrast, in patients relapsing after a first course, the response to a second course is 65%. 11,13 Until 2007, there were 2 preparations of hATG, namely, lymphoglobulin (Genzyme) and ATGAM (Pfizer). The most commonly used preparation of rATG (thymoglobulin, Genzyme) uses the same immunogen as lymophoglobulin; horses or rabbits are immunized with human thymocytes obtained at the time of cardiac surgery from newborn infants. rATG is more immunosuppressive than hATG; it results in more prolonged lymphopenia, 14 and it is more effective at preventing and treating acute renal allograft rejection. 15 We undertook a European study conducted by th...

Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study

“…36 However, in some countries (such as Brazil), rabbit ATG is the only formulation of ATG that is commercially available, which has been associated with inferior outcomes compared with horse ATG in comparative studies as first-line therapy, resulting in a greater number patients in need of salvage therapies. 37,38 The use of alternative donors as first salvage in younger patients with regimens including alemtuzumab is associated with excellent outcomes in retrospective studies. 39,40 However, for those who lack a histocompatible donor (related or unrelated) and are eligible for HSCT, investigating a haploidentical source of HSCs with post-transplantation Cy in a clinical research protocol is reasonable.…”

Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood

“…(ClinicalTrial.gov identifiers: NCT00662090) Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood 16 In addition, a number of non-randomized studies showed inferior results for rabbit-ATG in adults and children with aplastic anemia. [17][18][19] No published series of patients with aplastic anemia has shown that rabbit-ATG is superior to horse-ATG in the context of first-line IST. [16][17][18][19][20][21][22] To date, there have only been a few reports on the efficacy of IST with rabbit-ATG in patients with MDS.…”

“…[17][18][19] No published series of patients with aplastic anemia has shown that rabbit-ATG is superior to horse-ATG in the context of first-line IST. [16][17][18][19][20][21][22] To date, there have only been a few reports on the efficacy of IST with rabbit-ATG in patients with MDS. 10,23,24 In this study, we compared the outcome of IST using horse-ATG with that of IST using rabbit-ATG in a large series of children with RCC.…”

Immune suppression for childhood acquired aplastic anemia and myelodysplastic syndrome: where next?

“…Thus so far, none of the seven published studies comparing horse ATG and rabbit ATG has demonstrated superiority of rabbit ATG. [5][6][7][8][9][10][11] In five, rabbit ATG led to inferior overall survival or response rates [5][6][7]9,10 and in the other two 8,11 there was no significant difference between the two preparations. …”