Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Ayami Yoshimi,
  2. Charlotte M. Niemeyer,
  3. Monika M. Führer, and
  4. Brigitte Strahm
  1. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
  2. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
  3. Dr von Haunersches Kinderspital, Children Hospital of the Ludwig-Maximilians-University of Munich, Munich, Germany
  4. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany

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 However, lymphoglobulin (h-ATG; Genzyme) was withdrawn from the market in 2007.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.

Figure 1

Transplantation-free and overall survival. Transplantation-free survival (A) and overall survival (B) after IST with r-ATG and CSA compared with h-ATG and CSA. Second-line HSCT was considered as an event in the analysis of transplantation-free survival. HSCT was performed in 20 patients at a median of 258 days (range, 57-504) after IST in the r-ATG group and in 29 patients with a median of 625 days (range, 27-3718) after IST in the h-ATG group.

Authorship

Acknowledgments: The authors thank Sonja Behrendt, Carla Haid, and Stephanie Gehring for excellent support in data management.

Contribution: A.Y. designed the study, collected and analyzed the data, and wrote the manuscript; and C.M.N., M.M.F., and B.S. designed the study, collected the data, and critically revised and approved the final version of the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Ayami Yoshimi, MD, PhD, Division of Paediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany; e-mail: ayami.yoshimi{at}uniklinik-freiburg.de.

References