Successful Prevention of Acute Graft-versus-Host Disease Using Low-Dose Antithymocyte Globulin after Mismatched, Unrelated, Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia

Abstract

In this study, we investigated the effects of low-dose antithymocyte globulin (ATG, thymoglobulin) in the prevention of acute graft-versus-host disease (aGVHD) in mismatched, unrelated hematopoietic stem cell transplantations (uHSCTs) in patients with the single disease entity of acute myelogenous leukemia (AML). Patients (n = 103) with a variable risk for AML who received uHSCTs from available Asian and Caucasian donors were enrolled. First, we compared HLA-matched (group 1, n = 54) and HLA-mismatched (group 2, n = 49) transplantation patients. Then, we divided the patients in group 2, who had received transplants from allele(s)/antigen-mismatched donors, into 2 subgroups: patients who used ATG (group 3, n = 24) and those who did not (group 4, n = 25). To prevent the development of aGVHD, the patients in group 3 received ATG at a dose of 1.25 mg/kg body weight per day for 2 consecutive days, together with our standard regimen of methotrexate (MTX) and tacrolimus. The median CD34(+) cell infusion was 4.2 x 10(6)/kg (range: 1.2-34.4). The median patient age was 41 years (range: 16-57), and the median follow-up duration of patients who were event-free survivors was 23 months (range: 2-72). The overall incidences of aGVHD and chronic GVHD (cGVHD) were 38% and 56%, respectively. Of 48 evaluable patients in group 2, 10 (21%) developed moderate to severe aGVHD (grades II-IV). In contrast, 2 (8%) of the 24 patients in group 3 and 7 (29%) of the 24 evaluated patients in group 4 required therapy for aGVHD (grades II-IV; P = .038). The incidence of cGVHD was not different between groups 3 and 4. The estimated probabilities of overall survival (OS) and event-free survival (EFS) at 2 years for group 2 were 55% and 44%, respectively. In comparison, the estimated probabilities of OS and EFS at 2 years for groups 3 and 4 were 68% versus 38% (P = .043) and 58% versus 38% (P = .103), respectively. The overall cumulative incidence of nonrelapse mortality (NRM) was 29% in group 2. The cumulative incidence of NRM differed markedly between group 3 (16%; 95% confidence interval [CI], 4%-28%) and group 4 (44%, 95% CI, 34%-54%) (P = .013). We found no difference in cytomegalovirus (CMV) reactivation between groups 3 and 4. These results suggest that in mismatched uHSCT, a low dose of ATG (total 2.5 mg/kg) may prevent moderate to severe aGVHD, with comparable rates of relapse and CMV reactivation and a greatly decreased rate of NRM.

An addition of medium-dose ATG to conditioning regimens favours the long-term survival of patients with allogeneic hematopoietic stem cell transplantation

“…The 5-year survival of the complete HLA identical cases was 79.1% ± 8.78%, and the 5-year survival of the HLA mismatched patients was 52.0% ± 10.3%. Our results are consistent with those reported by Kim [28] 2009 and Mohty [29] 2010 in HLA-MUR transplantation.…”

High incidence of post transplant lymphoproliferative disorder after antithymocyte globulin-based conditioning and ineffective prediction by day 28 EBV-specific T lymphocyte counts

“…[29][30][31][32] Administration of rabbit-anti-human T lymphocyte antibodies has been increasingly used by transplant programs because the antibodies can partially prevent aGVHD and cGVHD without impacting rates of relapse and non-EBV infections (except when used at a high dose, for example, 48 mg/kg thymoglobulin). 9,20,[33][34][35][36][37][38][39][40][41] Thus, our findings that in patients conditioned with rabbit-ATG, the PTLD occurrence is relatively high (8.1%) and that the vast majority of PTLD's occurring before day 100 are important. This suggests that monitoring EBV DNAemia in the first 100 days is warranted, together with preemptive (at the time of high/rising EBV DNAemia) or prompt (early in the course of PTLD) administration of rituximab- [42][43][44] or EBV-specific T lymphocytes.…”

Favorable impact of pre-transplant ATG on outcomes of reduced-intensity hematopoietic cell transplants from partially mismatched unrelated donors

“…10 The utility of pre-transplant ATG as part of GVHD prophylaxis in patients receiving URD transplants has been debated for many years, and while the use of ATG appears to reduce the incidence of GVHD, benefits in terms of OS are less clear. [11][12][13][14]19 Further, both the preparation and dose of ATG appear to be important determinants of its impact on post-transplant outcomes. For rabbit ATG (Thymoglobulin), an early multicenter prospective study conducted by the GITMO group suggested that while a dose of 15 mg/kg was associated with a significant reduction in the risk of severe (grades III-IV) GVHD, this benefit was counterbalanced by an increased risk of opportunistic infections, resulting in similar OS for ATG and placebo groups.…”