Reduced Intensity versus Truly Nonmyeloablative Conditioning for Stem-Cell Transplant Recipients (2004)

The article by Le Blanc et al. analyzes the differences between two types of stem-cell transplantation (SCT) based on reduced-intensity conditioning (1). Traditionally, preparative regimens for SCT were used primarily for cytoreduction of the underlying malignancy and for immunosuppression of the host for prevention of allograft rejection. Graft-versus-leukemia (GVL) effects after SCT have been noted since the early days of transplantation, because the incidence of relapse was inversely correlated with the severity of graft-versus-host disease (GVHD). Unfortunately, transplant-related toxicity and mortality after conventional myeloablative SCT prevented larger scale application of SCT for elderly patients in need, although the indication for SCT occurs mostly in individuals older than 60 years of age. Furthermore, relapse continued to be the main cause of failure after SCT. In view of the above, available transplant procedures had relatively limited impact in curing patients with resistant hematologic malignancies. It was only in the 1980s that the use of donor lymphocyte infusions (DLI) was introduced to treat relapse after myeloablative SCT (2). The cumulative beneficial experience using DLI after SCT for treatment of established relapse and subsequently for relapse prevention suggested that durable engraftment of donor lymphocytes may be more effective than maximally tolerated doses of chemoradiotherapy. These observations led to the clinical application of nonmyeloablative stem-cell transplantation (NST), using the transplant procedure as a means to induce tolerance by engraftment of donor stem cells, followed by immunotherapy mediated by donor immunocompetent lymphocytes (2–4). Immunotherapy could be amplified by early discontinuation of cyclosporine (CsA) used for GVHD prevention, or by DLI. Because donor lymphocytes seemed to play a major role in eradication of tumor cells of host origins, it became obvious that the outcome of SCT could be improved by reducing the intensity of the conditioning, especially in elderly patients whose health precluded myeloablative conditioning. Consequently, various NST and reduced-intensity conditioning (RIC) regimens were introduced. Because many centers introduced their own modifications of NST, nomenclature became confusing, and no clear definitions exist to explain the differences between NST and RIC. If nonmyeloablative is defined as conditioning with no need for rescue, both types of regimens described in the article by Le Blanc and colleagues are nonmyeloablative, yet most patients treated with either of the two regimens are converted to 100% donor chimerism. Thus, regardless of the intensity of the conditioning, the final outcome is fully myeloablative. In fact, once host-versus-graft unresponsiveness is established, engraftment of alloreactive donor immunocompetent lymphocytes may eradicate all host-type hematopoietic cells, just like DLI does after conventional SCT. Consequently, although engraftment can be accomplished with minimal nonhematologic toxicity, the morbidity and mortality rates from acute and chronic GVHD remain high after both NST and especially RIC. Another factor that determines the success of allogeneic SCT is the so-called hematopoietic competition. When rejection and GVHD are neutralized, engraftment represents the result of competition between host and donor hematopoietic cells. Host stem cells may prevail in their own microenvironment, having a biologic advantage over donor stem cells. However, under truly nonmyeloablative conditioning, the number of residual host stem cells may exceed the number of stem cells infused, thus providing a relative advantage to host hematopoietic stem cells, and thus increasing the incidence of relapse and nonengraftment, as indeed was discovered in the article by Le Blanc et al. Because donor T cells play an important role in facilitating engraftment, especially in patients conditioned with a nonmyeloablative protocol, the intensity of postgrafting immunosuppression is also likely to play a role in engraftment and GVL effects. However, in the study by Le Blanc et al., both protocols consisted of posttransplant immunosuppression with CsA combined with mycophenolate mofetil. On the basis of the above, it seems reasonable that under conditions of intensive immunosuppression with CsA and mycophenolate mofetil combined, the difference in outcome between both regimens would be expected to increase. Indeed, the incidence of acute GVHD was higher in recipients of NST as compared with RIC (P<0.001). In contrast, the incidence of graft failure was higher in recipients of RIC (P=0.02). Another factor that may be relevant for comparing the anticipated outcome of patients prepared with NST or RIC is the role of residual lymphocytes and dendritic cells (DC) in the host. Logically, after RIC, higher proportions of residual host-type lymphocytes and DC may remain in the early posttransplant period. This would predict a higher risk of acute GVHD, because residual host DC directly presenting host class II can effectively stimulate alloreactive donor lymphocytes. The direct relationship between residual host DC and the incidence of GVHD was recently documented in a murine model of SCT (5). Likewise, residual host CD8 T cells can play an important role in decreasing GVHD in mixed chimeras. Although RIC may leave behind higher proportions of host-derived CD8+ T cells capable of decreasing GVHD, these may be eliminated by a potent immunosuppressive regimen using fludarabine with ionizing radiation or busulfan, both synergizing with fludarabine, and it seems reasonable to assume that putative veto cells of host origin were equally eliminated, both also receiving quite intensive posttransplant immunosuppressive treatment for prevention of GVHD. Considered together, the outcome of two protocols studied by Le Blanc et al. could be well predicted on the basis of the basic rules of immunology operating in mixed chimeras, which can be explained by the rule of “balanced equilibrium” (6). This rule predicts that the net effect in SCT between engraftment, rejection, GVHD, and GVL depends in part on the number of stem cells and immunocompetent lymphocytes present in the graft, in relationship with residual stem cells and immunocompetent lymphocytes remaining in the host (T cells and alloreactive natural killer cells) on the one hand, also considering hematopoietic competition, on the other. Regardless of the mechanism involved, RIC, whether truly nonmyeloablative, submyeloablative, or merely predominantly immunosuppressive, will lead to development of safer protocols associated with reduced procedure-related toxicity and mortality, thus providing a larger number of patients in need of SCT, normally excluded from SCT programs, with an option to benefit from a curative procedure.