Abstract
Rabbit anti-thymocyte globulin (ATG) is a key component of conditioning regimens for patients with aplastic anemia (AA) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Thymoglobuline (Thymo) is widely regarded as the standard formulation due to its extensive clinical adoption and inclusion in international guidelines, while Grafalon (Grafa) is also commonly used in clinical practice. Despite their differing manufacturing processes and immunogenic profiles, comparative data on clinical outcomes with these two ATG formulations in non-malignant settings remain limited. We conducted a large, retrospective analysis to evaluate the impact of Thymo versus Grafa on overall survival (OS), graft failure (GF), acute and chronic graft-versus-host disease (GVHD)—assessed at day +100 and at 24 months—and GVHD-free, relapse-free survival (GRFS) at 24 months in AA patients undergoing HSCT.
We analyzed data from 1603 patients who underwent first allogeneic HSCT for AA between 2011 and 2021, as recorded in the EBMT Registry. Transplants were conducted at 266 centers across 43 countries. 1080 patients received grafts from matched related donors (MRD) and 523 from 10/10 matched unrelated donors (MUD). Bone marrow (BM) was used as the stem cell source in 1116 patients (69.6%) and peripheral blood stem cells (PBSC) in 487 patients (30.4%). ATG formulation was inferred based on total cumulative dose: ≤15 mg/kg was categorized as Thymo (typical dose: 5–10 mg/kg) and 20–65 mg/kg as Grafa (typical dose: 30–60 mg/kg). Thymo was administered in 1313 patients (81.9%) and Grafa in 290 patients (18.1%). Kaplan-Meier estimates of OS and GRFS and cumulative incidences of aGvHD grade II-IV,and cGvHD and GF are tested by logrank and Gray tests respectively. Outcomes are given at 2 years after HCT.
In MRD transplants, OS rates were 86% for Grafa, and 88% for Thymo, respectively. Secondary GF rate at 24 months was 3% of patients receiving Grafa and 4% receiving Thymo. The incidence aGVHD was 7% in both groups. Chronic GVHD occurred in 5% of Grafa recipients versus 8% of Thymo recipients. GRFS at 24 months was 77% with Grafa and 80% with Thymo, with no statistically significant differences observed across any of these endpoints.
In MUD transplants, OS was 78% for Grafa, and 78% for Thymo, respectively. Secondary GF was 3% in Grafa-treated patients and 5% of Thymo-treated patients. The incidence of aGVHD by day 100 was 14% in the Grafa group and 19% in the Thymo group. At 24 months, cGVHD occurred in 26% of patients receiving Grafa and 19% receiving Thymo. GRFS was 63% with Grafa and 64% with Thymo, with no significant differences across all endpoints.
Analysis of stem cell source BM vs PBSC revealed no statistically significant difference on OS, GF, or GVHD between Grafa and Thymo. Two-year OS, stratified by stem cell source, was 86% for BM and 77% for PBSC in the Grafa group, and 86% for BM and 83% for PBSC in the Thymo group. Secondary GF was 4% for Thymo and 3% for Grafa, independent of stem cell source. The rate of aGVHD was 7% and 17% for BM and PBSC, respectively, in the Grafa group, and 11% and 12% for BM and PBSC in the Thymo group. At 24 months, cGVHD incidence with Grafa was 12% for BM and 16% for PBSC; for Thymo, it was 10% for BM and 16% for PBSC. GRFS for BM was 73% with Grafa and 76% with Thymo; for PBSC, GRFS was 67% with Grafa and 71% with Thymo.
Lastly, the effect of ATG dosage on outcomes was assessed in BM recipients treated with Grafa. Patients were stratified by cumulative dose administered, calculated based on a three-day dosing schedule: <36 mg (<12 mg/kg, n=102, 48.8%), 36–54 mg (12–18 mg/kg, n=78, 35.9%), and >54 mg (>18 mg/kg, n=32, 15.3%). OS was 84%, 92%, and 78%, respectively (p=0.15). The incidence of aGVHD was 4%, 8%, and 12%, respectively (p = 0.3). At 24 months, cGVHD occurred in 17%, 2%, and 17%, respectively (p = 0.027). GRFS was 72%, 80%, and 65%, respectively (p = 0.3).
In this large, registry-based cohort of AA patients undergoing HSCT, no significant differences were observed in OS, GF, GVHD incidence, or GRFS between Thymo and Grafa. However, Grafalon dosage appeared to influence outcomes, particularly with respect to chronic GVHD. These findings support the clinical equivalence of both rabbit ATG formulations in the setting of HSCT and suggest that ATG selection can be guided by institutional preference or availability without compromising patient outcomes.
