Partial T-Cell Depletion By Low-Dose Anti-Thymocyte Globulin to Reduce Severe Acute and Chronic Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

Background: T cells from a stem cell source are inevitably contaminated, and over 5.0×10⁴/kg T cells are thought to induce graft-versus-host disease (GVHD) in HLA-mismatched or haplo-identical stem cell transplantations (SCTs) [4]. To suppress GVHD reactions, a procedure for T-cell depletion (TCD) was developed over the past several decades, especially for HLA-mismatched and haplo-identical SCTs, which are at high risk for GVHD. To reduce the incidence of GVHD, a potentially effective agent is anti-thymocyte globulin (ATG), which is generally administered at a dose of ≥ 5-10 mg/kg. Based on data regarding the use of ATG for the treatment of aplastic anemia, we hypothesized that ATG might accommodate engraftment and inhibit GVHD. We attempted to use a lower dose of ATG to decrease non-relapse mortality (NRM) in Japanese patients undergoing an HLA-matched SCT.

Patients and method: We treated patients with hematological diseases who underwent an allogeneic SCT after March 2010 without or with 2.5 mg/kg ATG. The inclusion criteria for underlying disease included both hematological malignancies and bone marrow failures. All consecutive patients transplanted from an allogeneic related or unrelated donor were included. Cord blood transplantations were omitted from this analysis. The patients who underwent an SCT before February 2010 (n=20) were examined as the control group without ATG treatment. ATG was administered 1 day prior to the transplantation day at 2.5 mg/kg with 500 mg/body methylpredonisolone as a preconditioning procedure. GVHD prophylaxis, tacrolimus 0.03 mg/kg and short-term MTX (10-7-7 mg/m²) was adapted for both the ATG group and the control group.

Results: Thirty-nine (21 male, 18 female) recipients were recruited (median age 49 yrs, range 19-64 yrs). Their underlying diseases were acute myeloid leukemia (n=14), acute lymphoblastic leukemia (n=10), myelodysplastic syndrome (n=5), lymphoma (n=7), and myeloma, aplastic anemia, and other malignancy (n=1 each). Preparation regimens were myeloablative for 17 patients (14 cyclophosphamide [CY]/total body irradiation [TBI], two busulfan [BU]/CY, and another) and non-myeloablative for the other 22 patients (14 fludarabine/melphalan [Flu/Mel] and eight Flu/BU). All but one patient achieved engraftment, and one secondary graft failure was observed. The overall incidences of acute and chronic GVHD were 63.2% and 15.8% for the ATG-treated patients (40.0% and 25.0% for the control cohort), respectively. Acute GVHD (grades II to IV and III to IV) in the recipients who received ATG occurred in 21.1% and 0.0% (control cohort, 10.0% and 5.0%), respectively. The estimated probability of overall survival (OS) 2.5 yrs after transplantation was 77.8% for the ATG group (controls, 57.1%). The relapse rate 2.5 yrs after transplantation was 21.1% and 20.0% in the ATG and control groups, respectively. The NRM rate was decreased after ATG treatment: 25.0% vs. 10.5% (not significant). The causes of mortality with or without ATG were recurrent diseases (n=1 and 2), infection (n=1 and 0), and adverse events caused by transplant-related complication (n=1 and 5), respectively. No deaths due to acute or chronic GVHD occurred.

Discussion: Low-dose ATG could suppress the incidence of severe acute GVHD and chronic GVHD without increasing the NRM, although our study design did not have enough power to make a conclusion about the efficacy of low-dose ATG. However, partial T-cell depletion may be effective for HLA-matched SCT recipients. Our results show that ATG at 2.5 mg/kg can be used safely for the Japanese transplant population of HLA-matched donors. Low-dose ATG is a potential treatment to partially disempower T cells from a stem cell source, which are inevitably contaminated. Recent developments in the prophylaxis for GVHD, such as selective cytotoxic T-cell depletion by using a post-transplant CY regimen, are promising strategies to fully suppress T cells as the GVHD enhancer. Previous studies revealed the clinical efficacy of GVHD prophylaxis but did not clarify the significance of its survival benefit. Likewise, our present findings indicated a lack of survival benefit by ATG treatment in this small study. However, the low-dose ATG contributed to a reduction of severe GVHD. Although early mortality after transplantation is decreasing, late-onset comorbidity including chronic GVHD remains a significant problem.