Induction of graft-vs-malignancy as a primary therapeutic modality

An immune mediated graft-vs.-leukemia(GVL) effect is important to prevent relapse after allogeneic BMT. Relapse rates are lower in patients'with GVHD and higher with syngeneic or T-cell depleted transplants. Following high dose therapy, most patients with CML have evidence of minimal residual leukemia; but this is generally is undetectable after 6-12 months, presumably due to GVL. Patients relapsing with CML post BMT generally achieve durable complete remission by additional donor lymphocyte infusion (DLI). DLI is associated with acute GVHD in 50-80% of cases and marrow aplasia may develop. It may be possible to separate GVL and GVHD. T-cell doses <107/kg rarely produce GVHD, but may induce remission in some patients. Higher doses have a greater antileukemic effect, but also a higher rate of GVHD. CD8 depleted DLI are as effective for CML and myeloma with a lesser capacity to produce GVHD. T-cells transduced with Herpes virus thymidine kinase are rendered sensitive to ganciclovir; if DLI using these cells produces GVHD, it can be abrogated by ganciclovir treatment. Techniques to generate nonalloreactive T-cells or specific antileukemic T-cell clones are under study. GVL can be induced after a nonablative preparative regimen to achieve engraftment, allowing GVL to develop which can be enhanced if necessary by DLI. We reported fludarabine based chemotherapy is sufficiently immunosuppressive to prevent rejection and remissions have been achieved for patients with advanced acute leukemia, CML and CLL. This holds promise to reduce the morbidity and mortality associated with high dose chemoradiotherapy and potentially allows BMT in older or infirm patients who are not eligible for a standard high dose regimen.