Comparison of the efficacy of rabbit and horse antithymocyte globulin for the treatment of severe aplastic anemia in children

To the editor:

Immunosuppressive therapy (IST) with horse antithymocyte globulin (h-ATG) and cyclosporine (CSA) is an effective therapy for aplastic anemia (AA), resulting in a response rate of 60%-70% and an excellent survival for responders. However, lymphoglobulin (h-ATG; Genzyme) was withdrawn from the market in 2007. Because of the unavailability of h-ATG in most countries, the evaluation of rabbit ATG (r-ATG) as first-line therapy was stimulated. Marsh et al recently showed a low response to IST at 6 months (37%) in 35 patients who were given r-ATG (thymoglobulin; Genzyme).¹  The overall survival at 2 years was significantly lower (68%) compared with age- and disease-matched patients given h-ATG (n = 105, 86% P = .009). Furthermore, in a randomized controlled trial, Scheinberg et al showed an inferior response (37% vs 68% at 6 months, P < .001) and a decreased survival (76% vs 96%, 2 years, P = .04) after r-ATG (thymoglobulin) compared with h-ATG (ATGAM; Pfizer).²  In none of the published series r-ATG was found to be superior to h-ATG.^3,4  However, these series did not focus on outcome of children, so we compared both ATGs in children with AA.

Children (< 18 years of age) with severe AA diagnosed in Germany, Austria, and Switzerland and registered in the SAA-94 study between November 1993 and August 2011 received IST if no matched sibling donor was available.⁵  IST initially included h-ATG (lymphoglobulin 15 mg/kg/d for 8 days) and CSA as described previously.⁵  G-CSF was given if the neutrophil count was < 0.5 × 10⁹/L. Because of the unavailability of h-ATG, 32 patients received r-ATG (thymoglobulin 3.75 mg/kg/d for 5 days) since 2007. Approval for the study was obtained from the institutional review board of the Ludwig-Maximilians University of Munich. Written informed consent was provided by the parents of each patient.

Patients receiving r-ATG (n = 32) were matched for age (categorized as < 10 or ≥ 10 years) and disease severity (very severe or severe) with patients receiving h-ATG (n = 96). The median age of patients in the r-ATG group was 9.7 years; 10 patients had severe disease and 22 patients had very severe disease. The median follow-up times were 2.1 years (r-ATG) and 6.9 years (h-ATG; P < .001). Response was defined as described previously.⁵  The response rate at 6 months was 34% for r-ATG and 65% for h-ATG (P = .003). Although Marsh et al observed several late responses after r-ATG resulting in similar best response rates for r-ATG and h-ATG,¹  we observed only 2 late responses after r-ATG and a lower transplantation-free survival rate after IST with r-ATG compared with h-ATG (Figure 1A).¹  However, in contrast to previous studies, because of successful second-line hematopoietic stem cell transplantation (HSCT), the overall survival for both r-ATG and h-ATG was excellent (Figure 1B). The increased risk of death from infection after r-ATG that was observed by Marsh et al was not confirmed in our study.¹  These results demonstrate that in children with AA, IST with r-ATG is less effective than h-ATG. However, the majority of nonresponders could be rescued by HSCT. We conclude that, whenever possible, IST for treatment of children with AA should include h-ATG (ATGAM) and that, in the light of the improved results of unrelated HSCT, this procedure should be offered to all nonresponders at 6 months.^6,7  Even earlier HSCT should be considered in patients with prolonged severe neutropenia (0.2 × 10⁹/L) to avoid fatal infections.