CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation

Abstract

Donor lymphocyte infusions can reinduce complete remission in the majority of patients with chronic myelogenous leukemia (CML) who relapse into chronic phase after allogeneic bone marrow transplantation (BMT). Such infusions are associated with a high incidence of graft- versus-host disease (GVHD) and marrow aplasia. BMT using selective depletion of CD8+ lymphocytes from donor cells reduces the incidence of GVHD without an increase in leukemia relapse. We hypothesized that infusion of CD8-depleted donor peripheral blood lymphocytes could also reinduce complete remissions with a lesser potential to produce symptomatic GVHD in patients with CML who relapsed after allogeneic BMT. Ten patients with Ph(+) CML who relapsed a median of 353 days after BMT (range, 82 to 1,096 days) received donor lymphocyte infusions depleted of CD8+ cells. Nine patients received a single infusion and 1 received two infusions. Four patients were treated while in chronic phase with clonal evolution, 2 during accelerated phase, 3 during blast crisis, and 1 in a cytogenetic relapse. A mean of 0.9 +/- 0.3 x 10(8) mononuclear cells/kg were infused, containing 0.6 +/- 0.4 x 10(6) CD3+CD8+ cells/kg. Six patients achieved hematologic and cytogenetic remission at 4, 8, 11, 15, 39, and 54 weeks after lymphocyte infusion. Two patients developed > or = grade II acute GVHD, and 1 patient developed mild chronic GVHD. We conclude that donor lymphocyte infusions depleted of CD8+ cells can induce remissions with a low rate of severe acute GVHD in patients with CML who relapse after allogeneic BMT, supporting the hypothesis that CD8+ lymphocytes are important effectors of GVHD, but may not be essential for the graft-versus- leukemia effect against this disease. Further controlled studies are required to confirm these preliminary observations.

Ex vivo expanded cord blood CD4 T lymphocytes exhibit a distinct expression profile of cytokine‐related genes from those of peripheral blood origin

“…2 Although DLI frequently results in significant acute and/ or chronic graft-versus-host disease (GVHD), several groups have demonstrated that depletion of CD8 T cells from DLIs efficiently reduces the incidence and severity of GVHD while maintaining GVL activity. 3,4 Therefore, selective CD4 DLI is expected to provide an effective and low-toxicity therapeutic strategy for improving post-transplant immune function. Actually, selective CD4 DLI based on a recently established method for ex vivo T-cell expansion using anti-CD3 monoclonal antibody and interleukin (IL)-2 is now becoming established as a routine therapeutic means of resolving posttransplant immunological problems in Japan.…”

Analysis of a Chronic Myelogenous Leukemia Patient Vaccinated with Leukemic Dendritic Cells Following Autologous Peripheral Blood Stem Cell Transplantation

“…22) In relapse patients with CML, approximately 82% and 73% of the allo-BMT recipients infused with donor-derived T cells have been reported to enter cytogenetic and molecular remission, respectively. 9,23) Clinical trials with DCs in treating tumor-bearing patients have achieved success, as has been the case in animal models. [24][25][26][27] DCs are antigen-presenting cells that can enhance the generation of antigen-specific helper and cytotoxic T cells from naive T cells.…”

Mechanisms of the Graft‐versus‐Leukemia Reaction

“…In one study CD4 + but not CD8 + T cell and NK cell numbers after BMT were higher in patients who did not relapse, and superior NK function was also associated with continued remission [30]. As previously mentioned, there is some evidence from CD8 + depletion of BMT and donor lymphocytes that CD4 + T cells are more important than CD8 + T cells in the GVL response to CML [27][28][29]. However, the conclusions that CD4 + cells are necessary and sufficient to confer GVL must be balanced against the possibility that the GVL effect is conferred by a small number of residual CD8 + T cells or accompanying NK cells in the transplant.…”