Beneficial Role of Low-Dose Antithymocyte Globulin in Unrelated Stem Cell Transplantation for Adult Patients with Acquired Severe Aplastic Anemia: Reduction of Graft-versus-Host Disease and Improvement of Graft-versus-Host Disease–Free, Failure-Free Survival Rate

Abstract

Stem cell transplantation (SCT) from an unrelated donor (URD) is often considered in patients with severe aplastic anemia (SAA) whom immunosuppressive therapy failed and matched sibling donor is not available. To reduce the incidence of graft-versus-host disease (GVHD) in URD SCT, introducting antithymocyte globulin (ATG) into the conditioning regimen has been proposed. Although ATG was shown to play a role in reducing GVHD in a cohort with diverse hematologic diseases, its role in SAA remains uncertain. The aim of this study was to determine the efficacy and toxicity of ATG in URD SCT for adult patients with SAA. We investigated 83 adult patients with SAA who underwent URD SCT between 2003 and 2014. The transplantation strategy consisted of total body irradiation (total 800 cGy) and cyclophosphamide (total 100 mg/kg to 120 mg/kg), followed by tacrolimus and a short-term methotrexate. We divided patients into 2 groups: group 1 (n = 25), which received HLA-matched (8/8) bone marrow (BM) without ATG, and group 2 (n = 58), which received SCT from either an HLA-mismatched donor or peripheral blood (PB). Thereafter, group 2 was subdivided according to ATG use into group 2A (without ATG, n = 26), which served as a historical cohort, and group 2B (with ATG, n = 32). Rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France) was used in group 2B at a dose of 2.5 mg/kg. The median age of all patients was 30 years (range, 17 to 59 years). The incidence of GVHD was significantly lower in group 2B than group 2A, as demonstrated by the rate of grade II to IV acute GVHD at day 100 (31.2% versus 61.5%, P = .003) and the rate of chronic GVHD at 3 years (21.9% versus 65.4%, P = .002). The overall survival rates of the 3 groups were similar. However, GVHD-free, failure-free survival (GFFS) was significantly higher in group 2B than group 2A (P = .034). A multivariable model identified use of ATG as an independent factor affecting grades II to IV acute GVHD (hazard ratio [HR], 2.902; 95% confidence interval [CI], 1.417 to 5.942; P = .004), chronic GVHD (HR , 3.005; 95% CI, 1.279 to 7.059; P = .012), and GFFS (HR, 2.363; 95% CI, 1.162 to 4.805; P = .014). Toxicities, including infectious complications, were not different among the 3 groups. In conclusion, low-dose ATG (2.5 mg/kg) can reduce the incidence of acute and chronic GVHD and improve the quality of life in patients with SAA who receive stem cells from either an HLA-mismatched donor or PB; importantly, these benefits are achieved without increased toxicity. Furthermore, ATG can be considered in URD SCT from HLA-matched BM cells.

Allogeneic hematopoietic stem cell transplantation for aplastic anemia with pre‐transplant conditioning using fludarabine, reduced‐dose cyclophosphamide, and low‐dose thymoglobulin: A KSGCT prospective study

“…However, the incidence of chronic GVHD was relatively high. Park et al reported that the administration of ATG from day −3 to −2 at a dose of 1.25 mg/kg/day prevented chronic GVHD at a percentage of 21.9% . This was in HSCT from an unrelated donor for patients with AA, which was lower than the incidence in our study.…”

Optimal conditioning regimen for haplo‐identical stem cell transplantation in adult patients with acquired severe aplastic anemia: Prospective de‐escalation study of TBI and ATG dose

“…TBI‐600 cGy/Flu/intermediate‐dose ATG resulted in feasible outcomes of Haplo‐SCT for adult patients with SAA, indicated by the 91.7% OS and 78.4% GFFS rates. These outcomes were comparable to those of URD‐SCT reported in our previous study . In URD‐SCT for adult patients with SAA, OS, and GFFS rates were approximately 84.0%‐92.3% and 30.8%‐62.5% according to the use of ATG, respectively.…”

“…We previously reported early results from a pilot prospective study to determine the dose of TBI to be used in combination with 120 mg/kg of Cy as a conditioning regimen for URD‐SCT in adult patients with SAA, which demonstrated the superiority of 800 cGy of TBI compared to higher doses of TBI (1000 and 1200 cGy) . Later, we extended our experience, showing the feasibility of 800 cGy of TBI in combination with 120 mg/kg of Cy with engraftment of all patients . A TBI dose de‐escalation strategy for reducing transplant‐related toxicity without jeopardizing engraftment has also been reported …”

Comparable Outcomes of First-Line Hematopoietic Stem Cell Transplantation from Unrelated and Matched Sibling Donors in Adult Patients with Aplastic Anemia: A Retrospective Single-Center Study

“…In our study, all patients with AA received an ATG-based conditioning regimen, and GVHD prophylaxis consisted of CsA, mycophenolate mofetil, and low-dose methotrexate. Compared with a patient population treated with URD HSCT with total body irradiation and CY as the preparative regimen (grade II-IV aGVHD, 46%; cGVHD, 50%) [34], our URD patients had a 21.7% CI of aGVHD (no patients developed grade III-IV aGVHD) and a, 18.2% CI of cGVHD, and the use of ATG contributed to this low incidence [35,36]. A small number of pediatric AA patients underwent first-line URD transplantation, and the rate of GVHD was low with the alemtuzumab-based regimen (Flu + Cy + alemtuzumab) [12].…”