Lymphocyte recovery: an overlooked contribution to autologous stem cell transplant outcome

Abstract

In this issue of Cytotherapy, Hiwase et al. [1] provide evidence that the dose of lymphocytes infused in autologous stem cell transplantation (SCT) of multiple myeloma (MM) patients influences absolute lymphocyte recovery post-transplant and overall survival. The authors show that different factors influence CD34 and lymphocyte cell yield during leucapheresis and that the highest dose of lymphocytes is achieved by mobilization with granulocyte colony-stimulating factor (G-CSF) alone. According to the immune surveillance hypothesis, lymphocytes continually eliminate cancer cells [2]. The importance of immune surveillance is indirectly evidenced by observations correlating lymphocyte infiltration in solid tumors and lymphomas with a more favorable outcome than poor T-cell pathology [3]. The graft-versus-leukemia (GvL) response to residual disease after related or nonrelated allogeneic donor SCT is well established. The incidence of leukemia relapse is increased after aggressive graft-versus-host (GvH) disease prophylaxis or donor lymphocyte depletion, suggesting that allogeneic immunoresponses to residual leukemic cells, rather than the conditioning, cures leukemia after allogeneic SCT. In relapsed chronic myeloid leukemia, infusions of donor lymphocytes provide long-lasting remissions. The anti-leukemia effect is to a large extent mediated by T cells. However, in haplo-identical T-cell depleted transplants, natural killer (NK) KIR incompatibility between donor and recipient also reduces the risk of relapse in myeloid but not lymphoid malignancies [4]. NK cells are the first cells to recover in the early post-transplant period and define the dominant lymphocyte population. Slow recovery of the lymphocyte count has recently been proposed to predict an increased risk of relapse after allogeneic SCT [5,6]. Recovery of leukemia-specific immunity may also impact survival after autologous SCT. An absolute lymphocyte recovery of 500 cells/mL or more at day 15 after autologous peripheral blood hematopoietic SCT has been reported as a powerful, independent prognostic indicator of clinical outcome for patients both hematologic malignancies and solid tumors [7 9]. In autologous transplants, lymphocyte recovery post-transplant strongly correlates with the number of lymphocytes infused [7]. NK cells have anti-myeloma activity [8]; this argues in favor of the clinical significance of early NK cell engraftment as a manifestation of early reconstitution of anti-tumor immunosurveillance and a direct impact on lymphocyte reconstitution and survival post-autologous SCT. The paper by Hiwase et al. [1] is further evidence that recovery of lymphocyte immunity impacts survival after autologous SCT for MM. The correlation between the infused lymphocyte dose, lymphocyte recovery and improved survival suggests that stem cell mobilization and collection should be viewed not only as a means to achieve hematopoietic engraftment but also as a means to achieving immunologic recovery and thereby preventing relapse. The accumulating evidence linking prompt lymphocyte recovery after intensive chemotherapy with improved disease control and survival may be the best evidence in humans that immune surveillance has an important role in preventing relapse after high-dose chemotherapy treatment. These findings should prompt us to consider developing ways to enhance Tand NK-cell function after