Anti-Thymocyte Globulin At 6mg/Kg, Not 4.5mg/Kg, Protects From Severe Lethal Graft-Versus-Host Disease

Background: Allogeneic hematopoietic stem cell transplantation is a curative treatment for a number of hematological malignancies. Graft-versus-host disease (GVHD) remains a leading cause of morbidity and mortality. Rabbit anti-thymocyte globulin (ATG) is used to reduce the incidence of GVHD. However, dosing regimens and schedules vary.

Methods: We reviewed the medical records of 88 patients at our institution who received ATG at either 4.5 or 6.0mg/kg, in combination with tacrolimus and mycophenolate, prior to allogeneic stem cell transplantation between 2009 and 2011. ATG was administered over 3 days, finishing on day 0. We retrospectively evaluated the prophylactic effect of each ATG dosing regimen by measuring the incidence of severe (grade III-IV) acute GVHD and acute GVHD-associated mortality. We also measured relapse rate, overall survival (OS) and progression-free survival (PFS) for both groups.

Results: A total of 52 patients who received ATG at 4.5mg/kg (ATG1) were compared with 36 patients who received ATG at 6.0mg/kg (ATG2). The degree of HLA-mismatching was greater in ATG2 (39.1% mismatched unrelated donors) as compared to ATG1 (10% mismatched unrelated donors) (P=0.019) among 53 recipients from unrelated donors. Median follow up for ATG1 was 362 days, as compared to 512 days for ATG2. The cumulative incidence of grade III-IV acute GVHD at day 100 was 13.9% and 6.5% in the ATG1 and ATG2 groups, respectively (P=0.256). Specifically, 6 patients in ATG1 developed grade IV GHVD, as compared to 0 patients in ATG2. Acute GVHD-associated mortality was 7.7% and 0% in ATG1 and ATG2, respectively (P=0.141). All GVHD-associated deaths occurred in patients with grade IV GVHD. The relapse rates were comparable between ATG1 and ATG2 for both myeloablative (19% vs. 24%, P=0.349) and nonmyeloablative conditioning (13% vs. 9%, P=1.000). PFS at 1 year was slightly higher for ATG1 (52.8% vs. 45.5%, P=0.955), while OS at 1 year was not different between the two groups (53.7% vs 55.4%, P=0.779).

Conclusion: A small decrease in the prophylactic ATG dose (1.5mg/kg) had a significant clinical impact. An increased incidence of severe lethal acute GVHD was observed with 4.5mg/kg dosing despite a greater degree of HLA-matching. The 6.0mg/kg dosing prevented grade IV acute GVHD and associated mortality. Further research is warranted to find the optimal dosing regimen prior to allogeneic stem cell transplantation.