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Effective Graft-Versus-Leukemia Responses To Donor Lymphocyte Infusion Are Associated With Preexisting CD8 + T Cell Marrow Infiltrates

Year: 2010

Type: article

Abstract: Donor lymphocyte infusion is a highly effective treatment for relapsed CML after allogeneic hematopoietic stem cell transplant (HSCT), but predictors of response are unknown. In CML, marrow is the primary site of disease as well as a reservoir of high-avidity antigen-specific memory B and T cells that can recognize tumor antigens. We therefore examined serial bone marrow biopsies obtained before and after DLI for evidence of immune cell response from 31 patients with relapsed CML following allogeneic HSCT at our center between 1994-2001. All patients received CD4+DLI (3-10 × 107 CD4+ cells/kg) from the original stem cell donor. Twenty-four patients achieved complete cytogenetic remission following DLI, while 7 patients were non-responders. Marrow biopsies, collected prior to DLI, within the first 2-3 months following DLI and approximately 1 year after DLI were examined for cells expressing CD3, CD8, CD20 and CD138 by immunohistochemistry, and were also scored for cellularity. DLI responders demonstrated an increase in CD3+T cells following DLI compared to pre DLI (p=0.07), while no increase was observed among DLI non-responders. This infiltrate, appearing following DLI, consisted almost entirely of CD8+T cells. Significant changes in cells expressing CD20, CD138 were not observed. Examination of the pre-treatment marrow revealed that infiltration by leukemia-reactive T cells was closely associated with response to DLI. We detected a significantly increased percentage of marrow-infiltrative CD3+CD8+T cells in pre-treatment marrow biopsies of responders (median 8%, range 2-20) compared to non-responders (2.5%, range 1-2.5), p=0.013. Degree of marrow cellularity prior to DLI was also highly predictive of outcome. While responders demonstrated a 50% median cellularity prior to DLI, non-responders demonstrated more advanced relapse with median cellularity at the time of DLI of 93% (p=0.004). Of the responders, we observed that 3 patients had 70% or greater marrow cellularity, but also had 5% CD3+CD8+T cell infiltration, while all non-responders demonstrated <5% T cells, suggesting that T cells can overcome advanced tumor cellularity in some cases. These studies suggest that the presence of T cell infiltrates in the marrow microenvironment is a significant predictor of DLI response. This also implies that the effectiveness of DLI may be mediated in part through the enhancement of pre-existing GvL.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2009.12.459