Addition of Clofarabine to TLI/ATG Conditioning: Impact on Immune Reconstitution and Clinical Outcomes
Year: 2012
Type: article
Abstract: The use of reduced intensity conditioning with total lymphocyte irradiation (TLI) and anti-thymocyte globulin (ATG) in preparation for allogeneic transplantation has been shown to minimize the risk of GVHD through biasing of T cell reconstitution towards an inhibitory phenotype. However, disease relapse remains a concern. Clofarabine (Clo) is a second generation nucleoside analog with efficacy in hematological malignancies. In this study, we examined the combination of Clo, TLI and ATG with respect to T cell reconstitution and transplant outcomes. Sequential cohorts of 5 patients were treated with TLI and ATG alone or in conjunction with 20 mg/m2, 30 mg/m2 or 40 mg/m2 of Clo for 5 days. Twenty patients have been enrolled (5 AML/MDS, 2 ALL, 6 lymphoma, 2 CLL, 5 myeloma) and received HLA matched peripheral blood stem cells from related (N = 11) or unrelated donors (N = 9). Of 19 evaluable patients, 15 are alive with a median follow up of 665 days. Day 100 mortality was 0% for TLI and ATG and 10% for those receiving Clo. The maximum tolerated dose (MTD) of Clo was 30 mg/m2. Mean bone marrow donor chimerism was 92.5% at Day 30. T cell reconstitution studies demonstrated a decrease in CD4+ cells to <200 cells/uL persisting for more than 6 months, and a more than two fold increase in circulating CD56+ NK cells. No significant decrease in CD8 T cells in the early post-transplant period was seen. The mean percentage of regulatory T cells (CD4+/25+/FoxP3+) rose in the early post-transplant period following TLI and ATG (5.5 to 14.2% from baseline to day 30; p = 0.015), but not in those receiving Clo (8.1 to 6%; p = 0.15). A two fold increase in CD8+ T cells expressing IL-4 was seen at Day 30 in patients receiving TLI and ATG alone (p = 0.04); but not following Clo, TLI and ATG. Consistent with these findings, the incidence of grade II-IV GVHD was 0% and 42% in those receiving TLI and ATG alone or with Clo, respectively. cGVHD was seen in 20% and 42% of patients, respectively. In contrast, disease progression was seen in 60% of patients receiving TLI and ATG alone as compared to 27% receiving Clo, TLI, and ATG. In summary, the addition of Clo to TLI and ATG conditioning resulted in a decrease in circulating regulatory T cells, decreased CD8+ T cell expression of IL-4, and was associated with an increased risk of GVHD and the potential decrease in the risk of relapse in this pilot study.
Authors: B. Glotzbecker, H. Mills, J. Rosenblatt, R. Joyce, J. Levine, D. Tzachanis, M. Stevenson, E. Attar, K. Ballen, Y.-B. Chen, V. Boussiotis, J. Zwicker, K. Luptakova, J. Arnason, J. Bonhoff, C. Delaney, K. Conway, N. Giallombardo, J. Mortellite, D. Fitzgerald, S. O'Brien, C. McMahon, B. Vasir, D. Stroopinsky, T. Spitzer, D. Avigan
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W1964385569