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Critical factors in optimizing graft-versus-leukemia effect for relapsed leukemias.

To the Editor: Graft-versus-host disease has been shown to reduce the risk of relapse for acute leukemias, both lymphoid and myeloid, after an allogeneic transplantation, but donor lymphocyte infusion (DLI) is rarely effective in curing relapsed acute leukemias. One explanation for this phenomenon is the rapid progression of acute leukemias and accelerated chronic myeloid leukemia (CML). Chemotherapy alone is not effective in achieving a long-term cure in patients with these diseases. The approach used by Levine et al is probably the most rational one in that it uses cytoreduction before DLI. However, this approach failed to improve the disease-free or overall survival significantly. Graft-versus-host disease was associated with worse outcome and did not translate to a graft-versus-leukemia (GVL) effect. Given these findings, it would be tempting to hypothesise that the GVL effect does not cure relapsed leukemias. However, there are a few issues that need to be addressed in order to optimize the GVL effect. The concept of using mobilized DLI after chemotherapy is the same as a nonmyeloablative transplant. In that context, the timing of the DLI is probably critical. Bacigalupo et al reported that the impact of low-dose cyclosporine in reducing the relapse risk was in the first 10 days after transplantation. This is probably the period of maximal cytopenia and is the right milieu for the proliferation of donor effector cells with minimal or no competitive effect of host lymphocytes. Levine et al used DLI 10 to 14 days after the chemotherapy, which is not within this critical time period. On the basis of this observation, DLI should probably be scheduled within the first 3 days after chemotherapy, in accordance with the same principle as in a transplant procedure. One study suggested that patients with a greater burden of host lymphocytes respond less well to DLI. This concept is bolstered by the observation that after immunosuppression-based reduced-intensity conditioning, remission is achieved faster in CML patients than it is usually after DLI alone, and conversion to full donor chimerism in the T-cell lineage precedes a GVL response. Levine et al did not clarify how many patients received purine analog–based regimens and whether that influenced the outcome. There is probably a rationale for using purine analogs or other immunosuppressive drugs in the pre-DLI chemotherapy regimens to eliminate host lymphocytes that might impair the alloreactivity of donor lymphocytes by inducing tolerance. This brings in the question of T-cell chimerism and efficacy of DLI. Our limited experience with lineage-specific chimerism following both conventional and reduced-intensity transplantation suggests that donor T -cell engraftment lags behind granulocyte chimerism, which is often not picked up on chimerism analysis of whole blood or marrow. It would have been interesting to study the lineage-specific chimerism in relation to remission in the report by Levine et al. The final point we would like to highlight is that granulocyte colony-stimulating factor (CSF)–mobilized apheresis products might be important in preventing post-DLI aplasia, but the present body of literature suggests that granulocyte CSF might have a negative effect on alloreactivity. The use of granulocyte-macrophage CSF in mobilization, both before and after DLI, needs to be explored in an attempt to improve antigen presentation to the effector cells and improve the GVL effect.